Genetic Variant DHRS4L2:p.Ala117Val (chr14-23995075-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The NM_198083.4(DHRS4L2):c.350C>T(p.Ala117Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000577 in 1,612,940 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000062 ( 2 hom. )

Consequence

DHRS4L2
NM_198083.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.17

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 -2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.867

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DHRS4L2	NM_198083.4 link	c.350C>T	p.Ala117Val	missense_variant	Exon 3 of 8	ENST00000335125.11	NP_932349.2	Q6PKH6-1D5KJA1
DHRS4L2	NM_001193636.1 link	c.47C>T	p.Ala16Val	missense_variant	Exon 3 of 8		NP_001180565.1	D5KJA2A0A087WSZ6D5KJA1
DHRS4L2	NM_001193637.1 link	c.47C>T	p.Ala16Val	missense_variant	Exon 3 of 6		NP_001180566.1	D5KJA1F6VUV4
DHRS4L2	NM_001193635.1 link	c.222+4716C>T		intron_variant	Intron 4 of 8		NP_001180564.1	D5KJA1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DHRS4L2	ENST00000335125.11 link	c.350C>T	p.Ala117Val	missense_variant	Exon 3 of 8	1	NM_198083.4	ENSP00000334801.6		Q6PKH6-1

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151802

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:

0.0000442

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000438

AC:

AN:

251344

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135832

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000616

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000616

AC:

AN:

1461138

Hom.:

Cov.:

AF XY:

0.0000619

AC XY:

AN XY:

726836

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000139

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000639

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000198

AC:

AN:

151802

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74078

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:

0.0000442

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 18, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.350C>T (p.A117V) alteration is located in exon 3 (coding exon 3) of the DHRS4L2 gene. This alteration results from a C to T substitution at nucleotide position 350, causing the alanine (A) at amino acid position 117 to be replaced by a valine (V). 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

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.41

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

T;T;D;D;.

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.91

D;D;D;D;.

M_CAP

Uncertain

0.28

MetaRNN

Pathogenic

0.87

D;D;D;D;D

MetaSVM

Uncertain

0.60

PROVEAN

Benign

-2.0

N;.;D;D;D

REVEL

Pathogenic

0.90

Sift

Benign

0.080

T;.;D;D;D

Sift4G

Uncertain

0.032

D;D;D;D;D

Vest4

0.77

MVP

0.95

MPC

0.17

ClinPred

0.50

GERP RS

4.6

gMVP

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.19

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