rs1356154563

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_015474.4(SAMHD1):c.1293A>T(p.Leu431Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000559 in 1,611,320 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L431I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

SAMHD1
NM_015474.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.403

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SAMHD1	NM_015474.4 linkuse as main transcript	c.1293A>T	p.Leu431Phe	missense_variant	12/16	ENST00000646673.2
SAMHD1	NM_001363729.2 linkuse as main transcript	c.1293A>T	p.Leu431Phe	missense_variant	12/15
SAMHD1	NM_001363733.2 linkuse as main transcript	c.1293A>T	p.Leu431Phe	missense_variant	12/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SAMHD1	ENST00000646673.2 linkuse as main transcript	c.1293A>T	p.Leu431Phe	missense_variant	12/16		NM_015474.4	P1	Q9Y3Z3-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251284

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135850

show subpopulations

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:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000548

AC:

AN:

1459150

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726096

show subpopulations

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:

0.00000721

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Aicardi-Goutieres syndrome 5

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Apr 07, 2022	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 431 of the SAMHD1 protein (p.Leu431Phe). This variant is present in population databases (no rsID available, gnomAD 0.004%). This missense change has been observed in individual(s) with Aicardi-Goutieres syndrome (PMID: 30275001). 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: 559589). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	research	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	Aug 06, 2018	The SAMHD1 Leu431Phe (p.L431F) is an apparently novel missense variant that changes a single conserved amino acid from leucine to phenylalanine. Although this variant is not within either of the known functional protein domains, other nearby mutations have been associated with disease (Rice 2009, PMID: 19525956). This variant is absent from the ExAC database but observed in 1/24030 alleles in the GnomAD African population (allele frequency 0.00004). This variant has a score of 0.732 by the REVEL metapredictor (Ioannidis 2016, PMID: 27666373), which is below the ClinGen threshold cut-off (0.75) for application of ACMG/AMP in silico prediction evidence. This variant was observed in trans with a second missense variant (Ile201Asn), which is classified as likely pathogenic, in a patient with symptoms highly consistent with Aicardi-Goutieres syndrome. In summary, the Leu431Phe variant is currently considered a variant of uncertain significance based on ACMG/AMP criteria (PM2, PM3, PP4). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.34

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

T;.;.;.

Eigen

Benign

0.047

Eigen_PC

Benign

-0.041

FATHMM_MKL

Benign

0.25

LIST_S2

Uncertain

0.94

.;D;D;D

M_CAP

Pathogenic

0.35

MetaRNN

Uncertain

0.50

D;D;D;D

MetaSVM

Uncertain

0.41

MutationAssessor

Pathogenic

3.3

M;M;.;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-3.2

.;D;.;.

REVEL

Pathogenic

0.73

Sift

Uncertain

0.0050

.;D;.;.

Sift4G

Benign

0.14

.;T;.;.

Polyphen

0.90

P;.;.;.

Vest4

0.77

MutPred

0.44

Loss of helix (P = 0.0167);Loss of helix (P = 0.0167);Loss of helix (P = 0.0167);.;

MVP

0.90

MPC

1.4

ClinPred

0.88

GERP RS

1.7

Varity_R

0.66

gMVP

0.69

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over