Genetic Variant NM_144683.4:c.595G>C (chr17-28901077-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_144683.4(DHRS13):c.595G>C(p.Asp199His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000184 in 1,614,084 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

DHRS13
NM_144683.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.162

Variant links:

Genes affected

DHRS13 (HGNC:28326): (dehydrogenase/reductase 13) Predicted to enable NADP-retinol dehydrogenase activity. Predicted to be involved in retinal metabolic process. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

DHRS13 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 rank	MANE	Protein	UniProt
DHRS13	NM_144683.4 link	c.595G>C	p.Asp199His	missense_variant	Exon 4 of 5	ENST00000378895.9	NP_653284.2	Q6UX07-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DHRS13	ENST00000378895.9 link	c.595G>C	p.Asp199His	missense_variant	Exon 4 of 5	1	NM_144683.4	ENSP00000368173.4	Q6UX07-1
DHRS13	ENST00000394901.7 link	c.445G>C	p.Asp149His	missense_variant	Exon 3 of 4	1		ENSP00000378361.3	Q6UX07-2
DHRS13	ENST00000426464.2 link	c.352G>C	p.Asp118His	missense_variant	Exon 2 of 3	2		ENSP00000412826.2	Q6UX07-3
DHRS13	ENST00000581759.1 link	n.*35G>C		downstream_gene_variant		1

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000955

AC:

AN:

251200

Hom.:

AF XY:

0.0000736

AC XY:

AN XY:

135796

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:

0.000203

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000188

AC:

275

AN:

1461870

Hom.:

Cov.:

AF XY:

0.000182

AC XY:

132

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000228

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000145

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000279

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000112

Hom.:

Bravo

AF:

0.000125

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000123

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.595G>C (p.D199H) alteration is located in exon 4 (coding exon 4) of the DHRS13 gene. This alteration results from a G to C substitution at nucleotide position 595, causing the aspartic acid (D) at amino acid position 199 to be replaced by a histidine (H). 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

0.57

BayesDel_addAF

Benign

-0.075

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.015

T;.;.

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.52

LIST_S2

Uncertain

0.86

D;T;T

M_CAP

Benign

0.055

MetaRNN

Uncertain

0.47

T;T;T

MetaSVM

Benign

-0.51

MutationAssessor

Benign

1.1

L;.;.

PrimateAI

Uncertain

0.69

PROVEAN

Benign

0.38

N;N;N

REVEL

Uncertain

0.50

Sift

Benign

0.30

T;T;T

Sift4G

Benign

0.63

T;T;T

Polyphen

0.056

B;.;.

Vest4

0.63

MVP

0.65

MPC

0.96

ClinPred

0.089

GERP RS

4.4

Varity_R

0.19

gMVP

0.75

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