rs369587937

Positions:

• chr20-36905450-G-A
• chr20-36905450-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_015474.4(SAMHD1):​c.1324C>T​(p.Arg442Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000151 in 1,461,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: SAMHD1 NM_015474.4 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1 O:1
• Conservation: PhyloP100: 2.02

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 Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 20-36905450-G-A is Pathogenic according to our data. Variant chr20-36905450-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 126406.We mark this variant Likely_pathogenic, oryginal submissions are: {not_provided=1, Uncertain_significance=1, Pathogenic=2}. Variant chr20-36905450-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.1324C>T	p.Arg442Ter	stop_gained	12/16	ENST00000646673.2	NP_056289.2
SAMHD1	NM_001363729.2	c.1324C>T	p.Arg442Ter	stop_gained	12/15		NP_001350658.1
SAMHD1	NM_001363733.2	c.1324C>T	p.Arg442Ter	stop_gained	12/16		NP_001350662.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SAMHD1	ENST00000646673.2	c.1324C>T	p.Arg442Ter	stop_gained	12/16		NM_015474.4	ENSP00000493536	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251408 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135878

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: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000151 AC: 22 AN: 1461038 Hom.: 0 Cov.: 30 AF XY: 0.0000220 AC XY: 16 AN XY: 726892

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000647 Hom.: 0

Bravo AF: 0.0000151

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Aicardi-Goutieres syndrome 5 Pathogenic:1 Uncertain:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 01, 2023	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 126406). This premature translational stop signal has been observed in individual(s) with Aicardi-Goutieres syndrome (PMID: 19525956). This variant is present in population databases (rs369587937, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Arg442*) in the SAMHD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SAMHD1 are known to be pathogenic (PMID: 19525956, 22461318). -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	The SAMHD1 c.1324C>T (p.Arg442Ter) variant is a stop-gained variant that is predicted to cause premature termination of the protein. The p.Arg442Ter variant has been reported in one study in which it is found in one patient with Aicardi-Goutieres syndrome in a compound heterozygous state with a missense variant (Rice et al. 2009). Control data are unavailable for this variant, which is also not found in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium. Functional studies with the p.Arg442Ter variant transfected into HEK293 cells demonstrate that the variant does not affect the RNA binding function of the protein (Goncalves et al. 2012). Based on the limited evidence and the potential impact of stop-gained variants, the p.Arg442Ter variant is classified as a variant of unknown significance but suspicious for pathogenicity for Aicardi-Goutieres syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Jul 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	35
DANN	Uncertain	1.0
Eigen	Uncertain	0.35
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.83	D
MutationTaster	Benign	1.0	A
Vest4		0.99
GERP RS		3.2

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: rs369587937; hg19: chr20-35533853; COSMIC: COSV53428963; COSMIC: COSV53428963;