rs369587937

Variant names:

• chr20-36905450-G-A
• rs369587937
• NM_015474.4:c.1324C>T

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS3 PP5_Very_Strong

The NM_015474.4(SAMHD1):​c.1324C>T​(p.Arg442*) 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 Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV007104189: Functional studies suggest that this variant contributes to retained nucleic acid binding with impaired subcellular localization" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. R442R) has been classified as Likely benign. 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: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 2.02
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• Aicardi-Goutieres syndrome 5

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Genomics England PanelApp
• SAMHD1-related type 1 interferonopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Moyamoya disease

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• Aicardi-Goutieres syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial chilblain lupus

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• chilblain lupus 2

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• chilblain lupus

  Inheritance: AD Classification: NO_KNOWN Submitted by: Illumina

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV007104189: Functional studies suggest that this variant contributes to retained nucleic acid binding with impaired subcellular localization; however, further studies are needed (PMID: 22461318)
• PP5: Variant 20-36905450-G-A is Pathogenic according to our data. Variant chr20-36905450-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 126406.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015474.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SAMHD1	NM_015474.4	MANE Select	c.1324C>T	p.Arg442*	stop_gained	Exon 12 of 16	NP_056289.2
	SAMHD1	NM_001363729.2		c.1324C>T	p.Arg442*	stop_gained	Exon 12 of 15	NP_001350658.1	Q9Y3Z3-4
	SAMHD1	NM_001363733.2		c.1324C>T	p.Arg442*	stop_gained	Exon 12 of 16	NP_001350662.1	A0A2R8YCS7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SAMHD1	ENST00000646673.2	MANE Select	c.1324C>T	p.Arg442*	stop_gained	Exon 12 of 16	ENSP00000493536.2	Q9Y3Z3-1
	SAMHD1	ENST00000262878.5	TSL:1	c.1324C>T	p.Arg442*	stop_gained	Exon 12 of 15	ENSP00000262878.5	Q9Y3Z3-4
	SAMHD1	ENST00000866371.1		c.1462C>T	p.Arg488*	stop_gained	Exon 13 of 17	ENSP00000536430.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251408 AF XY: 0.0000147

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 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

African (AFR) AF: 0.0000299 AC: 1 AN: 33458

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000153 AC: 17 AN: 1111270

Other (OTH) AF: 0.0000166 AC: 1 AN: 60372

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000621 Hom.: 0

Bravo AF: 0.0000151

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
1	-	-	Aicardi-Goutieres syndrome 5 (2)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		2.0
Vest4		0.99
GERP RS		3.2
PromoterAI		-0.030	Neutral
Mutation Taster		=4/196	disease causing (ClinVar)

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

Other links and lift over

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