rs121434521

Variant names:

• chr20-36919456-T-C
• rs121434521
• NM_015474.4:c.760A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_015474.4(SAMHD1):​c.760A>G​(p.Met254Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SAMHD1 NM_015474.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1 O:1
• Conservation: PhyloP100: 4.66

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 8 ACMG points.

• PM1: In a domain HD (size 152) in uniprot entity SAMH1_HUMAN there are 8 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, 0.944

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SAMHD1	NM_015474.4	c.760A>G	p.Met254Val	missense_variant	Exon 7 of 16	ENST00000646673.2	NP_056289.2
SAMHD1	NM_001363729.2	c.760A>G	p.Met254Val	missense_variant	Exon 7 of 15		NP_001350658.1
SAMHD1	NM_001363733.2	c.760A>G	p.Met254Val	missense_variant	Exon 7 of 16		NP_001350662.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SAMHD1	ENST00000646673.2	c.760A>G	p.Met254Val	missense_variant	Exon 7 of 16		NM_015474.4	ENSP00000493536.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

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

Revision: criteria provided, single submitter

Submissions by phenotype

Aicardi-Goutieres syndrome 5 Pathogenic:1 Other:1

Jul 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

not specified Uncertain:1

Feb 05, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SAMHD1 c.760A>G (p.Met254Val) results in a conservative amino acid change located in the Metal dependent phosphohydrolases with conserved 'HD' motif (IPR003607) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251280 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.760A>G has been reported in the literature in an individual affected with Aicardi Goutieres Syndrome (Rice_2009). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function and the results indicate this variant affects protein function (Goncalves_2012, White_2017) however the implication of these findings for pathogenicity is unclear at this time. The following publications have been ascertained in the context of this evaluation (PMID: 22461318, 19525956, 28229507). ClinVar contains an entry for this variant (Variation ID: 4073). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.49	T;.;.;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.88	.;D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.94	D;D;D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Benign	1.9	M;M;.;M
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.9	.;D;.;.
REVEL	Pathogenic	0.85
Sift	Uncertain	0.011	.;D;.;.
Sift4G	Benign	0.085	.;T;.;.
Polyphen		0.87	P;.;.;.
Vest4		0.86
MutPred		0.78		Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);
MVP		0.94
MPC		0.78
ClinPred		0.88	D
GERP RS		5.8
Varity_R		0.60
gMVP		0.69

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: rs121434521; hg19: chr20-35547859;