Genetic Variant DHRS4L2:p.Val60Ala (chr14-23990232-T-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_198083.4(DHRS4L2):c.179T>C(p.Val60Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000561 in 1,612,504 control chromosomes in the GnomAD database, including 18 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00037 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00058 ( 16 hom. )

Consequence

DHRS4L2
NM_198083.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.88

Variant links:

Genes affected

DHRS4L2 (HGNC:19731): (dehydrogenase/reductase 4 like 2) This gene encodes a member of the short chain dehydrogenase reductase family. The encoded protein may be an NADPH dependent retinol oxidoreductase. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Aug 2010]

DHRS4L2 links:

DHRS4L1 (HGNC:):

DHRS4L1 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 Likely_benign. Variant got -4 ACMG points.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DHRS4L2	NM_198083.4 link	c.179T>C	p.Val60Ala	missense_variant	Exon 2 of 8	ENST00000335125.11	NP_932349.2	Q6PKH6-1D5KJA1
DHRS4L2	NM_001193635.1 link	c.95T>C	p.Val32Ala	missense_variant	Exon 4 of 9		NP_001180564.1	D5KJA1
DHRS4L2	NM_001193636.1 link	c.-125T>C		5_prime_UTR_variant	Exon 2 of 8		NP_001180565.1	D5KJA2A0A087WSZ6D5KJA1
DHRS4L2	NM_001193637.1 link	c.-125T>C		5_prime_UTR_variant	Exon 2 of 6		NP_001180566.1	D5KJA1F6VUV4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DHRS4L2	ENST00000335125.11 link	c.179T>C	p.Val60Ala	missense_variant	Exon 2 of 8	1	NM_198083.4	ENSP00000334801.6		Q6PKH6-1

Frequencies

GnomAD3 genomes

AF:

0.000375

AC:

AN:

151898

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.000289

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000662

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.000319

AC:

AN:

250786

Hom.:

AF XY:

0.000391

AC XY:

AN XY:

135652

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000318

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000655

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000529

Gnomad OTH exome

AF:

0.000979

GnomAD4 exome

AF:

0.000581

AC:

848

AN:

1460490

Hom.:

Cov.:

AF XY:

0.000578

AC XY:

420

AN XY:

726522

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.000447

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000174

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000682

Gnomad4 OTH exome

AF:

0.000679

GnomAD4 genome

AF:

0.000375

AC:

AN:

152014

Hom.:

Cov.:

AF XY:

0.000310

AC XY:

AN XY:

74292

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.000289

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000662

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.000513

Hom.:

ExAC

AF:

0.000255

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.179T>C (p.V60A) alteration is located in exon 2 (coding exon 2) of the DHRS4L2 gene. This alteration results from a T to C substitution at nucleotide position 179, causing the valine (V) at amino acid position 60 to be replaced by an alanine (A). 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

BayesDel_addAF

Benign

0.0025

BayesDel_noAF

Uncertain

0.10

CADD

Uncertain

DANN

Benign

0.96

DEOGEN2

Benign

0.074

T;D;D;.;.;.

Eigen

Benign

0.070

Eigen_PC

Benign

0.023

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.81

T;T;T;.;.;T

M_CAP

Uncertain

0.10

MetaRNN

Uncertain

0.55

D;D;D;D;D;D

MetaSVM

Uncertain

0.42

PROVEAN

Uncertain

-3.8

.;D;D;D;D;D

REVEL

Pathogenic

0.70

Sift

Uncertain

0.0010

.;D;D;D;D;D

Sift4G

Benign

0.070

T;D;D;D;T;T

Polyphen

0.36

.;.;.;.;B;B

Vest4

0.65

MVP

0.85

MPC

0.24

ClinPred

0.18

GERP RS

3.4

gMVP

0.68

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