Genetic Variant DHDH:p.Asp38Ala (chr19-48935022-A-C) – 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_014475.4(DHDH):c.113A>C(p.Asp38Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000642 in 1,576,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00067 ( 0 hom. )

Consequence

DHDH
NM_014475.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.33

Variant links:

Genes affected

DHDH (HGNC:17887): (dihydrodiol dehydrogenase) This gene encodes an enzyme that belongs to the family of dihydrodiol dehydrogenases, which exist in multiple forms in mammalian tissues and are involved in the metabolism of xenobiotics and sugars. These enzymes catalyze the NADP1-linked oxidation of transdihydrodiols of aromatic hydrocarbons to corresponding catechols. This enzyme is a dimeric dihydrodiol dehydrogenase, and it differs from monomeric dihydrodiol dehydrogenases in its high substrate specificity for trans-dihydrodiols of aromatic hydrocarbons in the oxidative direction. [provided by RefSeq, Jul 2008]

DHDH links:

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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=0.06529322).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DHDH	NM_014475.4 link	c.113A>C	p.Asp38Ala	missense_variant	Exon 2 of 7	ENST00000221403.7	NP_055290.1	Q9UQ10
DHDH	XM_047438617.1 link	c.113A>C	p.Asp38Ala	missense_variant	Exon 2 of 5		XP_047294573.1
DHDH	XM_017026598.2 link	c.-137A>C		5_prime_UTR_variant	Exon 2 of 7		XP_016882087.1
DHDH	XM_005258748.5 link	c.-60A>C		5_prime_UTR_variant	Exon 2 of 6		XP_005258805.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DHDH	ENST00000221403.7 link	c.113A>C	p.Asp38Ala	missense_variant	Exon 2 of 7	1	NM_014475.4	ENSP00000221403.2	Q9UQ10
DHDH	ENST00000522614.5 link	c.113A>C	p.Asp38Ala	missense_variant	Exon 2 of 5	5		ENSP00000428672.1	E5RGT8
DHDH	ENST00000523250.5 link	c.113A>C	p.Asp38Ala	missense_variant	Exon 2 of 5	5		ENSP00000428935.1	E5RFE0
DHDH	ENST00000520557.1 link	n.77A>C		non_coding_transcript_exon_variant	Exon 2 of 5	5		ENSP00000430360.1	H0YBU7

Frequencies

GnomAD3 genomes

AF:

0.000388

AC:

AN:

152068

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000691

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000366

AC:

AN:

201926

Hom.:

AF XY:

0.000293

AC XY:

AN XY:

109148

show subpopulations

Gnomad AFR exome

AF:

0.000165

Gnomad AMR exome

AF:

0.000213

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000627

Gnomad NFE exome

AF:

0.000695

Gnomad OTH exome

AF:

0.000202

GnomAD4 exome

AF:

0.000669

AC:

953

AN:

1424508

Hom.:

Cov.:

AF XY:

0.000636

AC XY:

449

AN XY:

705746

show subpopulations

Gnomad4 AFR exome

AF:

0.000123

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000816

Gnomad4 NFE exome

AF:

0.000817

Gnomad4 OTH exome

AF:

0.000711

GnomAD4 genome

AF:

0.000388

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74410

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.000691

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000494

Hom.:

Bravo

AF:

0.000363

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000466

AC:

ExAC

AF:

0.000190

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 19, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.113A>C (p.D38A) alteration is located in exon 2 (coding exon 2) of the DHDH gene. This alteration results from a A to C substitution at nucleotide position 113, causing the aspartic acid (D) at amino acid position 38 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

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.40

CADD

Uncertain

DANN

Benign

0.81

DEOGEN2

Benign

0.057

T;.;.

Eigen

Benign

0.031

Eigen_PC

Benign

0.12

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.85

T;D;D

M_CAP

Benign

0.0025

MetaRNN

Benign

0.065

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

L;.;.

PrimateAI

Benign

0.37

PROVEAN

Uncertain

-2.6

D;D;D

REVEL

Benign

0.19

Sift

Benign

0.13

T;T;T

Sift4G

Benign

0.51

T;T;T

Polyphen

0.18

B;.;.

Vest4

0.34

MVP

0.31

MPC

0.31

ClinPred

0.037

GERP RS

5.0

Varity_R

0.27

gMVP

0.50

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