Variant chr14-23959966-G-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_021004.4(DHRS4):c.371G>A(p.Gly124Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000249 in 1,607,778 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000014 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

DHRS4
NM_021004.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.07

Variant links:

Genes affected

DHRS4 (HGNC:16985): (dehydrogenase/reductase 4) Enables identical protein binding activity; oxidoreductase activity, acting on NAD(P)H, quinone or similar compound as acceptor; and oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor. Involved in several processes, including cellular ketone metabolic process; positive regulation of reactive oxygen species metabolic process; and steroid metabolic process. Located in nucleus and peroxisomal membrane. [provided by Alliance of Genome Resources, Apr 2022]

DHRS4 links:

DHRS4-AS1 (HGNC:23175): (DHRS4 antisense RNA 1)

DHRS4-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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
DHRS4	NM_021004.4 linkuse as main transcript	c.371G>A	p.Gly124Glu	missense_variant	3/8	ENST00000313250.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DHRS4	ENST00000313250.10 linkuse as main transcript	c.371G>A	p.Gly124Glu	missense_variant	3/8	1	NM_021004.4	P1	Q9BTZ2-1
DHRS4-AS1	ENST00000656462.1 linkuse as main transcript	n.213-18808C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0000135

AC:

AN:

148004

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000134

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:

251474

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1459774

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726312

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000135

AC:

AN:

148004

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

72308

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000134

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

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 19, 2022

The c.371G>A (p.G124E) alteration is located in exon 3 (coding exon 3) of the DHRS4 gene. This alteration results from a G to A substitution at nucleotide position 371, causing the glycine (G) at amino acid position 124 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Uncertain

0.044

BayesDel_noAF

Benign

-0.090

CADD

Benign

DANN

Benign

0.86

DEOGEN2

Benign

0.21

T;.;D;.

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.52

FATHMM_MKL

Uncertain

0.97

M_CAP

Uncertain

0.13

MetaRNN

Uncertain

0.57

D;D;D;D

MetaSVM

Uncertain

-0.20

MutationAssessor

Benign

1.4

L;L;.;L

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.55

PROVEAN

Pathogenic

-6.8

D;D;D;D

REVEL

Uncertain

0.37

Sift

Benign

0.030

D;D;D;D

Sift4G

Uncertain

0.025

D;D;T;D

Polyphen

0.031

B;B;B;B

Vest4

0.57

MutPred

0.58

Gain of solvent accessibility (P = 0.0171);Gain of solvent accessibility (P = 0.0171);Gain of solvent accessibility (P = 0.0171);Gain of solvent accessibility (P = 0.0171);

MVP

0.91

MPC

0.40

ClinPred

0.37

GERP RS

2.2

Varity_R

0.84

gMVP

0.71

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.33

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.33

Position offset: 37

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