rs369035155

Positions:

chr20-36935110-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_015474.4(SAMHD1):c.428G>A(p.Arg143His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,613,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R143C) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

SAMHD1
NM_015474.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4O:1

Conservation

PhyloP100: 7.91

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:

SAMHD1 (HGNC:):

SAMHD1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr20-36935111-G-A is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.946

PP5

Variant 20-36935110-C-T is Pathogenic according to our data. Variant chr20-36935110-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 126411.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-36935110-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SAMHD1	NM_015474.4 linkuse as main transcript	c.428G>A	p.Arg143His	missense_variant	4/16	ENST00000646673.2	NP_056289.2	Q9Y3Z3-1Q59H15
SAMHD1	NM_001363729.2 linkuse as main transcript	c.428G>A	p.Arg143His	missense_variant	4/15		NP_001350658.1
SAMHD1	NM_001363733.2 linkuse as main transcript	c.428G>A	p.Arg143His	missense_variant	4/16		NP_001350662.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SAMHD1	ENST00000646673.2 linkuse as main transcript	c.428G>A	p.Arg143His	missense_variant	4/16		NM_015474.4	ENSP00000493536.2		Q9Y3Z3-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251476

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1461680

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727144

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152098

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74288

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000498

Hom.:

Bravo

AF:

0.0000302

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Aicardi-Goutieres syndrome 5

Pathogenic:2Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 143 of the SAMHD1 protein (p.Arg143His). This variant is present in population databases (rs369035155, gnomAD 0.004%). This missense change has been observed in individuals with Aicardi-Gouti√®res syndrome (PMID: 19525956, 33683010; Invitae). ClinVar contains an entry for this variant (Variation ID: 126411). 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: 28229507, 29379009). This variant disrupts the p.Arg143 amino acid residue in SAMHD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19525956, 26431200, 28229507). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	Sep 25, 2018	[ACMG/AMP: PS3, PM2, PM5, PP3, PP5] This alteration is supported by well-established in vitro or in vivo functional studies to have a damaging effect on protein function or splicing [PS3], is absent from or rarely observed in large-scale population databases [PM2], is a novel missense change at an amino residue where a different missense change has been deemed to be pathogenic [PM5], is predicted to be damaging by multiple functional prediction tools [PP3], was reported as a pathogenic/likely pathogenic alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory) [PP5]. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 19, 2023	Published functional studies demonstrate that this variant has a damaging effect and leads to a loss of protein function (PMID: 28229507); This variant is associated with the following publications: (PMID: 19525956, 30487145, 23364794, 22056990, 22149989, 34055681, 33683010, 27943079, 29379009, 28229507, 32371413) -
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Mar 22, 2022	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.61

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.67

D;.;.;.

Eigen

Pathogenic

0.97

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

.;D;D;D

M_CAP

Pathogenic

0.68

MetaRNN

Pathogenic

0.95

D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.3

H;H;.;H

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-4.9

.;D;.;.

REVEL

Pathogenic

0.99

Sift

Pathogenic

0.0

.;D;.;.

Sift4G

Pathogenic

0.0

.;D;.;.

Polyphen

1.0

D;.;.;.

Vest4

0.98

MVP

0.99

MPC

1.6

ClinPred

1.0

GERP RS

5.1

Varity_R

0.92

gMVP

0.88

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