Genetic Variant DHRS4L2:p.Leu9Phe (chr14-23988972-C-T) – 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_198083.4(DHRS4L2):c.25C>T(p.Leu9Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,612,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

DHRS4L2
NM_198083.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.47

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:

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

DHRS4-AS1 links:

DHRS4L1 (HGNC:):

DHRS4L1 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=0.04952869).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DHRS4L2	NM_198083.4 link	c.25C>T	p.Leu9Phe	missense_variant	Exon 1 of 8	ENST00000335125.11	NP_932349.2	Q6PKH6-1D5KJA1
DHRS4L2	NM_001193635.1 link	c.45-1210C>T		intron_variant	Intron 3 of 8		NP_001180564.1	D5KJA1
DHRS4L2	NM_001193636.1 link	c.-175-1210C>T		intron_variant	Intron 1 of 7		NP_001180565.1	D5KJA2A0A087WSZ6D5KJA1
DHRS4L2	NM_001193637.1 link	c.-175-1210C>T		intron_variant	Intron 1 of 5		NP_001180566.1	D5KJA1F6VUV4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DHRS4L2	ENST00000335125.11 link	c.25C>T	p.Leu9Phe	missense_variant	Exon 1 of 8	1	NM_198083.4	ENSP00000334801.6		Q6PKH6-1

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151826

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460234

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726318

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151826

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74132

show subpopulations

Gnomad4 AFR

AF:

0.0000242

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:

0.00

Gnomad4 OTH

AF:

0.00

EpiCase

AF:

0.0000545

EpiControl

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

Nov 08, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.25C>T (p.L9F) alteration is located in exon 1 (coding exon 1) of the DHRS4L2 gene. This alteration results from a C to T substitution at nucleotide position 25, causing the leucine (L) at amino acid position 9 to be replaced by a phenylalanine (F). 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

-0.098

BayesDel_noAF

Benign

-0.38

CADD

Benign

0.058

DANN

Benign

0.57

DEOGEN2

Benign

0.019

T;T;.;.;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.17

T;T;.;.;T

M_CAP

Benign

0.019

MetaRNN

Benign

0.050

T;T;T;T;T

MetaSVM

Benign

-0.86

PROVEAN

Benign

-0.22

N;N;N;N;N

REVEL

Benign

0.083

Sift

Benign

0.72

T;T;T;T;T

Sift4G

Benign

0.70

T;T;T;T;T

Polyphen

0.0

.;.;.;B;B

Vest4

0.099

MVP

0.24

MPC

0.039

ClinPred

0.034

GERP RS

-2.1

gMVP

0.45

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