Genetic Variant SAMHD1:p.Arg164Gly (chr20-36935048-G-C) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_015474.4(SAMHD1):c.490C>G(p.Arg164Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R164Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SAMHD1
NM_015474.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.63

Publications

0 publications found

Variant links:

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: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
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

SAMHD1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM1

In a binding_site (size 0) in uniprot entity SAMH1_HUMAN

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.988

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SAMHD1	NM_015474.4 link	c.490C>G	p.Arg164Gly	missense_variant	Exon 4 of 16	ENST00000646673.2	NP_056289.2	Q9Y3Z3-1Q59H15
SAMHD1	NM_001363729.2 link	c.490C>G	p.Arg164Gly	missense_variant	Exon 4 of 15		NP_001350658.1
SAMHD1	NM_001363733.2 link	c.490C>G	p.Arg164Gly	missense_variant	Exon 4 of 16		NP_001350662.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SAMHD1	ENST00000646673.2 link	c.490C>G	p.Arg164Gly	missense_variant	Exon 4 of 16		NM_015474.4	ENSP00000493536.2		Q9Y3Z3-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461826

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727218

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111966

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.68

D;.;.;.

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.99

.;D;D;D

M_CAP

Pathogenic

0.88

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Pathogenic

0.93

MutationAssessor

Pathogenic

5.0

H;H;.;H

PhyloP100

5.6

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-6.9

.;D;.;.

REVEL

Pathogenic

0.88

Sift

Uncertain

0.0020

.;D;.;.

Sift4G

Uncertain

0.0090

.;D;.;.

Polyphen

1.0

D;.;.;.

Vest4

0.98

MutPred

0.92

Loss of methylation at R164 (P = 0.0258);Loss of methylation at R164 (P = 0.0258);Loss of methylation at R164 (P = 0.0258);Loss of methylation at R164 (P = 0.0258);

MVP

0.99

MPC

1.6

ClinPred

1.0

GERP RS

4.1

Varity_R

0.99

gMVP

0.93

Mutation Taster

=10/90

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over