rs1356154563

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5

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 Conflicting classifications of pathogenicity (no stars).

Frequency

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

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

SAMHD1
NM_015474.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

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 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 20-36905481-T-A is Pathogenic according to our data. Variant chr20-36905481-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 559589.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SAMHD1	NM_015474.4 link	c.1293A>T	p.Leu431Phe	missense_variant	Exon 12 of 16	ENST00000646673.2	NP_056289.2	Q9Y3Z3-1Q59H15
SAMHD1	NM_001363729.2 link	c.1293A>T	p.Leu431Phe	missense_variant	Exon 12 of 15		NP_001350658.1
SAMHD1	NM_001363733.2 link	c.1293A>T	p.Leu431Phe	missense_variant	Exon 12 of 16		NP_001350662.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SAMHD1	ENST00000646673.2 link	c.1293A>T	p.Leu431Phe	missense_variant	Exon 12 of 16		NM_015474.4	ENSP00000493536.2		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: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Aicardi-Goutieres syndrome 5

Pathogenic:1Uncertain:1

Jun 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; external communication). 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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SAMHD1 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Aug 06, 2018

UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

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;.;.

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