chr20-36930783-A-T

Position:

chr20-36930783-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5

The NM_015474.4(SAMHD1):c.602T>A(p.Ile201Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000132 in 1,613,372 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. IAGLCHDLG201S) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

SAMHD1
NM_015474.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:10U:1O:1

Conservation

PhyloP100: 9.21

Variant links:

Genes affected

SAMHD1 (HGNC:15925): (SAM and HD domain containing deoxynucleoside triphosphate triphosphohydrolase 1) This gene may play a role in regulation of the innate immune response. The encoded protein is upregulated in response to viral infection and may be involved in mediation of tumor necrosis factor-alpha proinflammatory responses. Mutations in this gene have been associated with Aicardi-Goutieres syndrome. [provided by RefSeq, Mar 2010]

SAMHD1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a domain HD (size 152) in uniprot entity SAMH1_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) in NM_015474.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.935

PP5

Variant 20-36930783-A-T is Pathogenic according to our data. Variant chr20-36930783-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 30605.We mark this variant Likely_pathogenic, oryginal submissions are: {not_provided=1, Likely_pathogenic=3, Pathogenic=4, Uncertain_significance=1}. Variant chr20-36930783-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SAMHD1	NM_015474.4 linkuse as main transcript	c.602T>A	p.Ile201Asn	missense_variant	5/16	ENST00000646673.2
SAMHD1	NM_001363729.2 linkuse as main transcript	c.602T>A	p.Ile201Asn	missense_variant	5/15
SAMHD1	NM_001363733.2 linkuse as main transcript	c.602T>A	p.Ile201Asn	missense_variant	5/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SAMHD1	ENST00000646673.2 linkuse as main transcript	c.602T>A	p.Ile201Asn	missense_variant	5/16		NM_015474.4	P1	Q9Y3Z3-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251364

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135858

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000144

AC:

210

AN:

1461248

Hom.:

Cov.:

AF XY:

0.000118

AC XY:

AN XY:

727012

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000188

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152124

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74290

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000112

Hom.:

Bravo

AF:

0.0000302

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:10Uncertain:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Aicardi-Goutieres syndrome 5

Pathogenic:4Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2015	- -
Likely pathogenic, criteria provided, single submitter	research	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	Aug 06, 2018	The SAMHD1 Ile201Asn (p.I201N) variant has previously been reported in two unrelated individuals with autosomal recessive Aicardi-Goutieres syndrome 5, along with a second deleterious variant (Rice 2009, PMID: 19525956; Ramesh 2010, PMID: 20653736). It is located within the HD (histidine-aspartate) domain of the encoded protein and was observed in 6/111618 alleles in the GnomAD European (Non-Finnish) population (allele frequency 0.00005). This variant has a score of 0.901 by the REVEL metapredictor (Ioannidis 2016, PMID: 27666373), which exceeds the ClinGen threshold cut-off (0.75) for application of ACMG/AMP in silico prediction evidence. This variant was observed in trans with a second missense variant (Leu431Phe), which is classified as a VUS, in a patient with symptoms highly consistent with Aicardi-Goutieres syndrome. In summary, the Ile201Asn variant meets ACMG/AMP criteria to be classified as likely pathogenic (PM1, PM2, PP3, PP4). -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 30, 2023	This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 201 of the SAMHD1 protein (p.Ile201Asn). This variant is present in population databases (rs138603088, gnomAD 0.005%). This missense change has been observed in individuals with SAMHD1-related conditions (PMID: 19525956, 20653736, 27604406). ClinVar contains an entry for this variant (Variation ID: 30605). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SAMHD1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SAMHD1 function (PMID: 22461318, 22973040, 28229507). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The SAMHD1 c.602T>A (p.Ile201Asn) variant has been reported in at least three studies in which it was found in a homozygous state in two individuals, in a compound heterozygous state in one individual, and in a heterozygous state in four individuals, all with Aicardi-Goutieres syndrome (Rice et al. 2009; Ramesh et al. 2010; Crow et al. 2015). In one of these families, the variant was reported to cosegregate with disease. The p.Ile201Asn variant was absent from 450 control alleles (Ravenscroft et al. 2011) and is reported at a frequency of 0.00004 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies in HEK 293T cells showed that the variant resulted in reduced protein expression compared to wildtype and catalytic inactivity (Hofmann et al. 2012). Localization studies for the variant protein are conflicting; Hofmann et al. (2012) reported a normal nuclear localization in HEK 293T cells compared to wild type whereas Goncalves et al. (2012) reported cytosolic localization of the variant protein in HeLa cells. Based on the collective evidence, the p.Ile201Asn variant is classified as likely pathogenic for Aicardi-Goutieres syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Aicardi Goutieres syndrome

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 21, 2024	Variant summary: SAMHD1 c.602T>A (p.Ile201Asn) results in a non-conservative amino acid change located in the HD/PDEase domain (IPR003607) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251364 control chromosomes. c.602T>A has been reported in the literature in multiple homozygous or compound heterozygous individuals affected with Aicardi Goutieres Syndrome (e.g. Ramesh_2010, Haskell_2018, Yarbrough_2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in significantly reduced ability to block viral infection in transfected U937 cells (White_2017). The following publications have been ascertained in the context of this evaluation (PMID: 30275001, 20653736, 28229507, 27604406). ClinVar contains an entry for this variant (Variation ID: 30605). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 02, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 17, 2018	The p.Ile201Asn variant in SAMHD1 has been reported in 4 individuals with Aicard i-Goutieres syndrome: 1 who was homozygous for the variant, 2 who carried additi onal rare missense variants in SAMHD1, and 1 who also carried a frameshift varia nt in SAMHD1 (Rice 2009, Ramesh 2010, Yarbrough 2016, Haskell 2018). It segregat ed with disease in 2 affected individuals from 1 family who had symptoms of Aica rdi-Goutieres syndrome but did not have neurological involvement (Yarbrough 2016 ). In addition, it was identified in the heterozygous state in a mother and son with early onset chilblain lupus (Ravenscroft 2010). It has also been identified in 6/113690 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org ) and reported in ClinVar (Variation ID # 30605). In summary, although additiona l studies are required to fully establish its clinical significance, this varian t meets criteria to be classified as likely pathogenic for autosomal recessive A icardi-Goutieres syndrome. ACMG/AMP criteria applied: PM2, PM3, PP1_Moderate, PP 3, PS3_Supporting. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 07, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 16, 2020	Observed in the heterozygous state without a second SAMHD1 variant identified in a mother and son with familial chilblain lupus in the published literature (Ravenscroft et al., 2011); Published functional studies demonstrate a damaging effect through altered cellular localization, reduced protein expression, and catalytic inactivity (Goncalves et al., 2012; Hofmann et al., 2012; White et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21204240, 20653736, 30275001, 27604406, 22149989, 24335234, 25604658, 22639057, 22973040, 28229507, 19525956, 22461318, 22953710, 24035396, 22691373, 24183309) -

Chilblain lupus 2

Pathogenic:1Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.90

D;.;.;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.98

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.99

.;D;D;D

M_CAP

Pathogenic

0.49

MetaRNN

Pathogenic

0.93

D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.4

H;H;.;H

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-6.9

.;D;.;.

REVEL

Pathogenic

0.90

Sift

Pathogenic

0.0

.;D;.;.

Sift4G

Pathogenic

0.0010

.;D;.;.

Polyphen

1.0

D;.;.;.

Vest4

0.95

MVP

0.95

MPC

1.9

ClinPred

1.0

GERP RS

6.0

Varity_R

0.99

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over