chr20-36930783-A-T

Variant names:

• chr20-36930783-A-T
• rs138603088
• NM_015474.4:c.602T>A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3 PP3_Moderate PP5_Very_Strong

The NM_015474.4(SAMHD1):​c.602T>A​(p.Ile201Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000132 in 1,613,372 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000433787: Functional studies in HEK 293T cells showed that the variant resulted in reduced protein expression compared to wildtype and catalytic inactivity (Hofmann et al. 2012)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: SAMHD1 NM_015474.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11 O:1
• Conservation: PhyloP100: 9.21
• Publications: 16 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 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000433787: Functional studies in HEK 293T cells showed that the variant resulted in reduced protein expression compared to wildtype and catalytic inactivity (Hofmann et al. 2012).; SCV000937623: Experimental studies have shown that this missense change affects SAMHD1 function (PMID: 22461318, 22973040, 28229507).; SCV000966862: PS3_Supporting.; SCV005204113: The most pronounced variant effect results in significantly reduced ability to block viral infection in transfected U937 cells (White_2017). PMID: 20653736; SCV001776971: Published functional studies demonstrate a damaging effect through altered cellular localization, reduced protein expression, and catalytic inactivity (PMID: 22461318, 22973040, 28229507)
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.935
• PP5: Variant 20-36930783-A-T is Pathogenic according to our data. Variant chr20-36930783-A-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 30605.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.602T>A	p.Ile201Asn	missense	Exon 5 of 16	NP_056289.2
	SAMHD1	NM_001363729.2		c.602T>A	p.Ile201Asn	missense	Exon 5 of 15	NP_001350658.1	Q9Y3Z3-4
	SAMHD1	NM_001363733.2		c.602T>A	p.Ile201Asn	missense	Exon 5 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.602T>A	p.Ile201Asn	missense	Exon 5 of 16	ENSP00000493536.2	Q9Y3Z3-1
	SAMHD1	ENST00000262878.5	TSL:1	c.602T>A	p.Ile201Asn	missense	Exon 5 of 15	ENSP00000262878.5	Q9Y3Z3-4
	SAMHD1	ENST00000866371.1		c.602T>A	p.Ile201Asn	missense	Exon 5 of 17	ENSP00000536430.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152124 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 251364 AF XY: 0.0000221

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000144 AC: 210 AN: 1461248 Hom.: 0 Cov.: 30 AF XY: 0.000118 AC XY: 86 AN XY: 727012

African (AFR) AF: 0.0000299 AC: 1 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53368

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

European-Non Finnish (NFE) AF: 0.000188 AC: 209 AN: 1111478

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152124 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74290

African (AFR) AF: 0.00 AC: 0 AN: 41424

American (AMR) AF: 0.00 AC: 0 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000112 Hom.: 0

Bravo AF: 0.0000302

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Aicardi-Goutieres syndrome 5 (5)
3	-	-	Aicardi Goutieres syndrome (3)
2	-	-	not provided (2)
1	-	-	Aicardi-Goutieres syndrome 5;C3280721:Chilblain lupus 2 (1)
1	-	-	Chilblain lupus 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.90	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.4	H
PhyloP100		9.2
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-6.9	D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.95
MVP		0.95
MPC		1.9
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.99
gMVP		0.89
Mutation Taster		=201/99	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: rs138603088; hg19: chr20-35559186;