20-36930868-A-C

Position:

• chr20-36930868-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_015474.4(SAMHD1):​c.517T>G​(p.Tyr173Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 U:1
• Conservation: PhyloP100: 2.24

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 6 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, 0.846

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SAMHD1	NM_015474.4	c.517T>G	p.Tyr173Asp	missense_variant	5/16	ENST00000646673.2	NP_056289.2
SAMHD1	NM_001363729.2	c.517T>G	p.Tyr173Asp	missense_variant	5/15		NP_001350658.1
SAMHD1	NM_001363733.2	c.517T>G	p.Tyr173Asp	missense_variant	5/16		NP_001350662.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SAMHD1	ENST00000646673.2	c.517T>G	p.Tyr173Asp	missense_variant	5/16		NM_015474.4	ENSP00000493536	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 23, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.85	D;.;.;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Pathogenic	0.98	.;D;D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.85	D;D;D;D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Pathogenic	3.1	M;M;.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-7.7	.;D;.;.
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0060	.;D;.;.
Sift4G	Uncertain	0.010	.;D;.;.
Polyphen		1.0	D;.;.;.
Vest4		0.88
MutPred		0.68		Gain of disorder (P = 0.0842);Gain of disorder (P = 0.0842);Gain of disorder (P = 0.0842);Gain of disorder (P = 0.0842);
MVP		0.98
MPC		1.9
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.89
gMVP		0.82

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: rs1555835829; hg19: chr20-35559271;