chr20-36892937-T-C

Position:

chr20-36892937-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_015474.4(SAMHD1):c.1876A>G(p.Met626Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,613,954 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M626K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

SAMHD1
NM_015474.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.11

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:

TLDC2 (HGNC:16112): (TBC/LysM-associated domain containing 2) Predicted to be involved in response to oxidative stress. Predicted to act upstream of or within negative regulation of oxidative stress-induced neuron death. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

TLDC2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.04783207).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SAMHD1	NM_015474.4 linkuse as main transcript	c.1876A>G	p.Met626Val	missense_variant	16/16	ENST00000646673.2
TLDC2	NM_080628.3 linkuse as main transcript	c.*93T>C		3_prime_UTR_variant	7/7	ENST00000217320.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SAMHD1	ENST00000646673.2 linkuse as main transcript	c.1876A>G	p.Met626Val	missense_variant	16/16		NM_015474.4	P1	Q9Y3Z3-1
TLDC2	ENST00000217320.8 linkuse as main transcript	c.*93T>C		3_prime_UTR_variant	7/7	1	NM_080628.3	P1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152066

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

249228

Hom.:

AF XY:

0.00000741

AC XY:

AN XY:

134896

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:

0.0000269

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.0000108

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152066

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74266

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Aicardi-Goutieres syndrome 5

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 13, 2022

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 626 of the SAMHD1 protein (p.Met626Val). This variant is present in population databases (rs767155031, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with SAMHD1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.042

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.45

CADD

Benign

0.0080

DANN

Benign

0.32

DEOGEN2

Benign

0.058

T;.;.

Eigen

Benign

-2.1

Eigen_PC

Benign

-2.2

FATHMM_MKL

Benign

0.0044

LIST_S2

Benign

0.39

.;T;T

M_CAP

Benign

0.058

MetaRNN

Benign

0.048

T;T;T

MetaSVM

Uncertain

-0.19

MutationAssessor

Benign

-0.69

N;.;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.26

REVEL

Benign

0.23

Polyphen

0.0

B;.;.

MutPred

0.40

Loss of MoRF binding (P = 0.103);.;.;

MVP

0.25

MPC

0.52

ClinPred

0.014

GERP RS

-7.4

Varity_R

0.021

gMVP

0.24

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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