rs138603088

chr20-36930783-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9 U:1 O:1
• Conservation: PhyloP100: 9.21

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]

ACMG classification

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: {Pathogenic=3, not_provided=1, Likely_pathogenic=3, Uncertain_significance=1}. Variant chr20-36930783-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152124 Hom.: 0 Cov.: 32

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: 6 AN: 251364 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135858

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.: 0 Cov.: 30 AF XY: 0.000118 AC XY: 86 AN XY: 727012

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: 3 AN: 152124 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74290

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.: 0

Bravo AF: 0.0000302

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:9 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Aicardi-Goutieres syndrome 5 Pathogenic:4 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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. -
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). -
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:2

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. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 02, 2020	- -

not provided Pathogenic:2

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) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 07, 2022	- -

Chilblain lupus 2 Pathogenic:1 Uncertain:1

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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.28
Cadd	Pathogenic	27
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.90	D;.;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.93	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.4	H;H;.;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.87	D
Polyphen		1.0	D;.;.;.
Vest4		0.95
MVP		0.95
MPC		1.9
ClinPred		1.0	D
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

Other links and lift over

dbSNP: rs138603088; hg19: chr20-35559186;