Genetic Variant NM_021004.4:c.285C>G (chr14-23955191-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_021004.4(DHRS4):c.285C>G(p.Asp95Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

DHRS4
NM_021004.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.569

Publications

0 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 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
DHRS4	NM_021004.4 link	c.285C>G	p.Asp95Glu	missense_variant	Exon 2 of 8	ENST00000313250.10	NP_066284.2	Q9BTZ2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DHRS4	ENST00000313250.10 link	c.285C>G	p.Asp95Glu	missense_variant	Exon 2 of 8	1	NM_021004.4	ENSP00000326219.5		Q9BTZ2-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000205

AC:

AN:

1461084

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726826

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33458

American (AMR)

AF:

0.00

AC:

AN:

44670

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26072

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

AN:

86152

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53366

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5712

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111618

Other (OTH)

AF:

0.00

AC:

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 10, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.285C>G (p.D95E) alteration is located in exon 2 (coding exon 2) of the DHRS4 gene. This alteration results from a C to G substitution at nucleotide position 285, causing the aspartic acid (D) at amino acid position 95 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

Uncertain

0.53

BayesDel_addAF

Uncertain

0.039

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

T;.;D;.;.;.;.

Eigen

Benign

-0.090

Eigen_PC

Benign

-0.15

FATHMM_MKL

Benign

0.60

M_CAP

Uncertain

0.087

MetaRNN

Uncertain

0.44

T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.13

MutationAssessor

Benign

1.5

L;L;.;L;L;L;L

PhyloP100

0.57

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-3.7

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

REVEL

Benign

0.24

Sift

Benign

0.040

D;T;T;D;D;D;D

Sift4G

Benign

0.080

T;T;T;T;T;T;T

Polyphen

0.84

P;P;P;P;.;D;D

Vest4

0.33

MutPred

0.49

Gain of ubiquitination at K92 (P = 0.0756);Gain of ubiquitination at K92 (P = 0.0756);Gain of ubiquitination at K92 (P = 0.0756);Gain of ubiquitination at K92 (P = 0.0756);Gain of ubiquitination at K92 (P = 0.0756);Gain of ubiquitination at K92 (P = 0.0756);Gain of ubiquitination at K92 (P = 0.0756);

MVP

0.86

MPC

0.39

ClinPred

0.98

GERP RS

-0.047

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.65

gMVP

0.42

Mutation Taster

=81/19

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over