dbSNP rs12507599: DTHD1:p.Arg677Cys (chr4-36308427-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001170700.3(DTHD1):c.2029C>T(p.Arg677Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.257 in 1,551,206 control chromosomes in the GnomAD database, including 52,327 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.26 ( 5281 hom., cov: 32)

Exomes 𝑓: 0.26 ( 47046 hom. )

Consequence

DTHD1
NM_001170700.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.521

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0010963976).

BP6

Variant 4-36308427-C-T is Benign according to our data. Variant chr4-36308427-C-T is described in ClinVar as [Benign]. Clinvar id is 1168071.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.362 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DTHD1	NM_001170700.3 link	c.2029C>T	p.Arg677Cys	missense_variant	Exon 7 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.2029C>T	p.Arg677Cys	missense_variant	Exon 7 of 10	5	NM_001170700.3	ENSP00000492542.1	A0A1W2PR94
DTHD1	ENST00000507598.5 link	c.1774C>T	p.Arg592Cys	missense_variant	Exon 6 of 9	1		ENSP00000424426.1	D6RB49
DTHD1	ENST00000456874.3 link	c.1654C>T	p.Arg552Cys	missense_variant	Exon 6 of 9	1		ENSP00000401597.2	Q6ZMT9-1
DTHD1	ENST00000357504.7 link	c.1159C>T	p.Arg387Cys	missense_variant	Exon 6 of 9	2		ENSP00000350103.3	Q6ZMT9-2

Frequencies

GnomAD3 genomes

AF:

0.260

AC:

39550

AN:

151962

Hom.:

5285

Cov.:

show subpopulations

Gnomad AFR

AF:

0.254

Gnomad AMI

AF:

0.374

Gnomad AMR

AF:

0.321

Gnomad ASJ

AF:

0.261

Gnomad EAS

AF:

0.340

Gnomad SAS

AF:

0.378

Gnomad FIN

AF:

0.224

Gnomad MID

AF:

0.241

Gnomad NFE

AF:

0.240

Gnomad OTH

AF:

0.257

GnomAD3 exomes

AF:

0.287

AC:

45202

AN:

157372

Hom.:

6839

AF XY:

0.291

AC XY:

24225

AN XY:

83208

show subpopulations

Gnomad AFR exome

AF:

0.257

Gnomad AMR exome

AF:

0.346

Gnomad ASJ exome

AF:

0.256

Gnomad EAS exome

AF:

0.362

Gnomad SAS exome

AF:

0.380

Gnomad FIN exome

AF:

0.232

Gnomad NFE exome

AF:

0.240

Gnomad OTH exome

AF:

0.268

GnomAD4 exome

AF:

0.256

AC:

358745

AN:

1399126

Hom.:

47046

Cov.:

AF XY:

0.260

AC XY:

179415

AN XY:

690060

show subpopulations

Gnomad4 AFR exome

AF:

0.259

Gnomad4 AMR exome

AF:

0.341

Gnomad4 ASJ exome

AF:

0.257

Gnomad4 EAS exome

AF:

0.282

Gnomad4 SAS exome

AF:

0.380

Gnomad4 FIN exome

AF:

0.228

Gnomad4 NFE exome

AF:

0.244

Gnomad4 OTH exome

AF:

0.271

GnomAD4 genome

AF:

0.260

AC:

39566

AN:

152080

Hom.:

5281

Cov.:

AF XY:

0.265

AC XY:

19704

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.254

Gnomad4 AMR

AF:

0.321

Gnomad4 ASJ

AF:

0.261

Gnomad4 EAS

AF:

0.340

Gnomad4 SAS

AF:

0.377

Gnomad4 FIN

AF:

0.224

Gnomad4 NFE

AF:

0.240

Gnomad4 OTH

AF:

0.256

Alfa

AF:

0.247

Hom.:

6699

Bravo

AF:

0.267

TwinsUK

AF:

0.234

AC:

869

ALSPAC

AF:

0.242

AC:

934

ESP6500AA

AF:

0.246

AC:

340

ESP6500EA

AF:

0.259

AC:

823

ExAC

AF:

0.277

AC:

6868

Asia WGS

AF:

0.346

AC:

1209

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.44

CADD

Benign

9.1

DANN

Benign

0.83

DEOGEN2

Benign

0.052

.;.;.;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.052

LIST_S2

Benign

0.67

T;T;T;T

MetaRNN

Benign

0.0011

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

.;.;.;M

PrimateAI

Benign

0.23

PROVEAN

Uncertain

-3.5

.;D;D;D

REVEL

Benign

0.092

Sift

Benign

0.088

.;T;T;T

Sift4G

Uncertain

0.0030

.;D;D;D

Polyphen

0.0040

.;B;.;.

Vest4

0.097, 0.043, 0.046

ClinPred

0.022

GERP RS

2.0

Varity_R

0.065

gMVP

0.28

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over