dbSNP rs747817328: DTHD1:p.Arg200Ser (chr4-36284302-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001170700.3(DTHD1):c.598C>A(p.Arg200Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000325 in 1,536,974 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign 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. R200C) has been classified as Likely benign.

Frequency

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

Exomes 𝑓: 0.0000029 ( 0 hom. )

Consequence

DTHD1
NM_001170700.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.186

Variant links:

Genes affected

DTHD1 (HGNC:37261): (death domain containing 1) This gene encodes a protein which contains a death domain. Death domain-containing proteins function in signaling pathways and formation of signaling complexes, as well as the apoptosis pathway. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2012]

DTHD1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0407463).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DTHD1	NM_001170700.3 link	c.598C>A	p.Arg200Ser	missense_variant	Exon 2 of 10	ENST00000639862.2	NP_001164171.2	Q6ZMT9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DTHD1	ENST00000639862.2 link	c.598C>A	p.Arg200Ser	missense_variant	Exon 2 of 10	5	NM_001170700.3	ENSP00000492542.1	A0A1W2PR94
DTHD1	ENST00000507598.5 link	c.343C>A	p.Arg115Ser	missense_variant	Exon 1 of 9	1		ENSP00000424426.1	D6RB49
DTHD1	ENST00000456874.3 link	c.223C>A	p.Arg75Ser	missense_variant	Exon 1 of 9	1		ENSP00000401597.2	Q6ZMT9-1
DTHD1	ENST00000357504.7 link	c.17+2273C>A		intron_variant	Intron 1 of 8	2		ENSP00000350103.3	Q6ZMT9-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000718

AC:

AN:

139282

Hom.:

AF XY:

0.0000134

AC XY:

AN XY:

74690

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:

0.0000440

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000289

AC:

AN:

1384870

Hom.:

Cov.:

AF XY:

0.00000439

AC XY:

AN XY:

683354

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000280

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000379

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152104

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000147

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000481

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.028

DANN

Benign

0.46

DEOGEN2

Benign

0.00065

.;.;T

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0099

LIST_S2

Benign

0.22

T;T;T

M_CAP

Benign

0.0035

MetaRNN

Benign

0.041

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-0.69

.;.;N

PrimateAI

Benign

0.23

PROVEAN

Benign

0.77

.;N;N

REVEL

Benign

0.017

Sift

Benign

0.36

.;T;T

Sift4G

Benign

0.60

.;T;T

Vest4

0.018, 0.025

MutPred

0.24

.;.;Loss of sheet (P = 0.0817);

MVP

0.014

ClinPred

0.070

GERP RS

-3.8

Varity_R

0.075

gMVP

0.21

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

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over