19-48936062-A-G

Position:

chr19-48936062-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The ENST00000221403.7(DHDH):c.233A>G(p.Gln78Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000522 in 1,608,614 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000048 ( 0 hom. )

Consequence

DHDH
ENST00000221403.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.40

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.28255802).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
DHDH	NM_014475.4 linkuse as main transcript	c.233A>G	p.Gln78Arg	missense_variant	3/7	ENST00000221403.7	NP_055290.1
DHDH	XM_047438617.1 linkuse as main transcript	c.233A>G	p.Gln78Arg	missense_variant	3/5		XP_047294573.1
DHDH	XM_017026598.2 linkuse as main transcript	c.-17A>G		5_prime_UTR_variant	3/7		XP_016882087.1
DHDH	XM_005258748.5 linkuse as main transcript	c.30+951A>G		intron_variant			XP_005258805.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
DHDH	ENST00000221403.7 linkuse as main transcript	c.233A>G	p.Gln78Arg	missense_variant	3/7	1	NM_014475.4	ENSP00000221403	P1
DHDH	ENST00000522614.5 linkuse as main transcript	c.233A>G	p.Gln78Arg	missense_variant	3/5	5		ENSP00000428672
DHDH	ENST00000523250.5 linkuse as main transcript	c.202+951A>G		intron_variant		5		ENSP00000428935
DHDH	ENST00000520557.1 linkuse as main transcript	c.166+951A>G		intron_variant, NMD_transcript_variant		5		ENSP00000430360

Frequencies

GnomAD3 genomes

AF:

0.0000921

AC:

AN:

152046

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000590

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:

0.0000441

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.0000546

AC:

AN:

238132

Hom.:

AF XY:

0.0000772

AC XY:

AN XY:

129552

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000150

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:

0.0000745

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000481

AC:

AN:

1456568

Hom.:

Cov.:

AF XY:

0.0000552

AC XY:

AN XY:

724154

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000296

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:

0.0000441

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.0000921

AC:

AN:

152046

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74266

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000590

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.000480

Bravo

AF:

0.000295

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 18, 2022

The c.233A>G (p.Q78R) alteration is located in exon 3 (coding exon 3) of the DHDH gene. This alteration results from a A to G substitution at nucleotide position 233, causing the glutamine (Q) at amino acid position 78 to be replaced by an arginine (R). 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

Benign

0.19

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.029

T;.

Eigen

Benign

0.054

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.67

T;T

M_CAP

Benign

0.0028

MetaRNN

Benign

0.28

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

L;.

MutationTaster

Benign

1.0

D;N;N

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-2.2

N;D

REVEL

Benign

0.087

Sift

Benign

0.074

T;D

Sift4G

Benign

0.14

T;T

Polyphen

0.37

B;.

Vest4

0.20

MutPred

0.71

Loss of ubiquitination at K80 (P = 0.0518);Loss of ubiquitination at K80 (P = 0.0518);

MVP

0.22

MPC

0.61

ClinPred

0.15

GERP RS

3.9

Varity_R

0.30

gMVP

0.52

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