20-36892946-C-G

Variant names:

• chr20-36892946-C-G
• NM_015474.4:c.1867G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015474.4(SAMHD1):​c.1867G>C​(p.Asp623His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D623G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SAMHD1 NM_015474.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: -0.487
• Publications: 0 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]

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08422887).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SAMHD1	NM_015474.4	c.1867G>C	p.Asp623His	missense_variant	Exon 16 of 16	ENST00000646673.2	NP_056289.2
TLDC2	NM_080628.3	c.*102C>G		3_prime_UTR_variant	Exon 7 of 7	ENST00000217320.8	NP_542195.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SAMHD1	ENST00000646673.2	c.1867G>C	p.Asp623His	missense_variant	Exon 16 of 16		NM_015474.4	ENSP00000493536.2
TLDC2	ENST00000217320.8	c.*102C>G		3_prime_UTR_variant	Exon 7 of 7	1	NM_080628.3	ENSP00000217320.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Aicardi Goutieres syndrome Uncertain:1

Apr 19, 2025

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	13
DANN	Benign	0.96
DEOGEN2	Benign	0.060	T;.;.
Eigen	Benign	-0.93
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.81	.;T;T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.084	T;T;T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	1.6	L;.;.
PhyloP100		-0.49
PrimateAI	Benign	0.34	T
REVEL	Benign	0.22
Polyphen		0.0050	B;.;.
MutPred		0.23		Gain of MoRF binding (P = 0.0199);.;.;
MVP		0.78
MPC		0.62
ClinPred		0.17	T
GERP RS		-0.99
Varity_R		0.10
gMVP		0.41
Mutation Taster		=100/0	polymorphism

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

hg19: chr20-35521349;