rs387906948

Positions:

• chr20-36935111-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PM5 PP3_Strong PP5_Moderate

The NM_015474.4(SAMHD1):​c.427C>T​(p.Arg143Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000253 in 1,461,566 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R143H) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: SAMHD1 NM_015474.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 3.62

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr20-36935110-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 20-36935111-G-A is Pathogenic according to our data. Variant chr20-36935111-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 30604.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr20-36935111-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SAMHD1	NM_015474.4	c.427C>T	p.Arg143Cys	missense_variant	4/16	ENST00000646673.2	NP_056289.2
SAMHD1	NM_001363729.2	c.427C>T	p.Arg143Cys	missense_variant	4/15		NP_001350658.1
SAMHD1	NM_001363733.2	c.427C>T	p.Arg143Cys	missense_variant	4/16		NP_001350662.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SAMHD1	ENST00000646673.2	c.427C>T	p.Arg143Cys	missense_variant	4/16		NM_015474.4	ENSP00000493536.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251476 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135912

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000253 AC: 37 AN: 1461566 Hom.: 0 Cov.: 30 AF XY: 0.0000206 AC XY: 15 AN XY: 727098

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: 0.0000315

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000457 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Aicardi-Goutieres syndrome 5 Pathogenic:2 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2009	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 25, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 143 of the SAMHD1 protein (p.Arg143Cys). This variant is present in population databases (rs387906948, gnomAD 0.0009%). This missense change has been observed in individual(s) with Aicardi-Goutieres syndrome (PMID: 19525956). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 30604). 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. Experimental studies have shown that this missense change affects SAMHD1 function (PMID: 26431200, 28229507). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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, 28229507, 29379009, 33683010; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.67	D;.;.;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	1.0	.;D;D;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.8	H;H;.;H
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-7.9	.;D;.;.
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	.;D;.;.
Sift4G	Pathogenic	0.0	.;D;.;.
Polyphen		1.0	D;.;.;.
Vest4		0.95
MutPred		0.98		Loss of helix (P = 0.0626);Loss of helix (P = 0.0626);Loss of helix (P = 0.0626);Loss of helix (P = 0.0626);
MVP		0.99
MPC		1.7
ClinPred		1.0	D
GERP RS		4.1
Varity_R		0.95
gMVP		0.90

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: rs387906948; hg19: chr20-35563514; COSMIC: COSV99483885; COSMIC: COSV99483885;