19-48939452-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014475.4(DHDH):c.370A>G(p.Ile124Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,459,274 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

DHDH
NM_014475.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.22

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15677851).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
DHDH	NM_014475.4 linkuse as main transcript	c.370A>G	p.Ile124Val	missense_variant	4/7	ENST00000221403.7
DHDH	XM_017026598.2 linkuse as main transcript	c.121A>G	p.Ile41Val	missense_variant	4/7
DHDH	XM_047438617.1 linkuse as main transcript	c.370A>G	p.Ile124Val	missense_variant	4/5
DHDH	XM_005258748.5 linkuse as main transcript	c.34A>G	p.Ile12Val	missense_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
DHDH	ENST00000221403.7 linkuse as main transcript	c.370A>G	p.Ile124Val	missense_variant	4/7	1	NM_014475.4	P1
DHDH	ENST00000522614.5 linkuse as main transcript	c.370A>G	p.Ile124Val	missense_variant	4/5	5
DHDH	ENST00000523250.5 linkuse as main transcript	c.203-2988A>G		intron_variant		5
DHDH	ENST00000520557.1 linkuse as main transcript	c.170A>G	p.His57Arg	missense_variant, NMD_transcript_variant	3/5	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250752

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135564

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1459274

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

725400

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000505

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.01e-7

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

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

Dec 13, 2022

The c.370A>G (p.I124V) alteration is located in exon 4 (coding exon 4) of the DHDH gene. This alteration results from a A to G substitution at nucleotide position 370, causing the isoleucine (I) at amino acid position 124 to be replaced by a valine (V). 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

0.12

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.57

Cadd

Benign

Dann

Benign

0.63

DEOGEN2

Benign

0.037

T;.

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.11

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.79

T;D

M_CAP

Benign

0.0014

MetaRNN

Benign

0.16

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.47

N;.

MutationTaster

Benign

1.0

D;N;N

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.33

N;N

REVEL

Benign

0.045

Sift

Benign

0.58

T;T

Sift4G

Benign

0.71

T;T

Polyphen

0.017

B;.

Vest4

0.066

MutPred

0.61

Loss of sheet (P = 0.0054);Loss of sheet (P = 0.0054);

MVP

0.25

MPC

0.11

ClinPred

0.10

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.095

gMVP

0.16

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