20-36892951-A-T

Position:

• chr20-36892951-A-T

Variant summary

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

The NM_015474.4(SAMHD1):​c.1862T>A​(p.Phe621Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SAMHD1 NM_015474.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.63

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]

TLDC2 (HGNC:16112): (TBC/LysM-associated domain containing 2) Predicted to be involved in response to oxidative stress. Predicted to act upstream of or within negative regulation of oxidative stress-induced neuron death. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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	UniProt
SAMHD1	NM_015474.4	c.1862T>A	p.Phe621Tyr	missense_variant	16/16	ENST00000646673.2
TLDC2	NM_080628.3	c.*107A>T		3_prime_UTR_variant	7/7	ENST00000217320.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SAMHD1	ENST00000646673.2	c.1862T>A	p.Phe621Tyr	missense_variant	16/16		NM_015474.4	P1
TLDC2	ENST00000217320.8	c.*107A>T		3_prime_UTR_variant	7/7	1	NM_080628.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Aicardi-Goutieres syndrome 5 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 15, 2020

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. 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with SAMHD1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces phenylalanine with tyrosine at codon 621 of the SAMHD1 protein (p.Phe621Tyr). The phenylalanine residue is weakly conserved and there is a small physicochemical difference between phenylalanine and tyrosine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T;.;.
Eigen	Benign	0.16
Eigen_PC	Benign	0.022
FATHMM_MKL	Uncertain	0.89	D
M_CAP	Uncertain	0.23	D
MetaRNN	Uncertain	0.44	T;T;T
MetaSVM	Uncertain	0.26	D
MutationAssessor	Uncertain	2.1	M;.;.
MutationTaster	Benign	1.0	N;D
PrimateAI	Uncertain	0.51	T
Polyphen		1.0	D;.;.
MutPred		0.26		Gain of phosphorylation at F621 (P = 0.0047);.;.;
MVP		0.87
MPC		1.5
ClinPred		0.88	D
GERP RS		3.7
Varity_R		0.23
gMVP		0.35

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-35521354;