19-48939593-G-C

Position:

chr19-48939593-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The ENST00000221403.7(DHDH):c.511G>C(p.Gly171Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,565,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000093 ( 0 hom., cov: 28)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

DHDH
ENST00000221403.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.93

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 Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.968

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
DHDH	NM_014475.4 linkuse as main transcript	c.511G>C	p.Gly171Arg	missense_variant	4/7	ENST00000221403.7	NP_055290.1
DHDH	XM_017026598.2 linkuse as main transcript	c.262G>C	p.Gly88Arg	missense_variant	4/7		XP_016882087.1
DHDH	XM_047438617.1 linkuse as main transcript	c.511G>C	p.Gly171Arg	missense_variant	4/5		XP_047294573.1
DHDH	XM_005258748.5 linkuse as main transcript	c.175G>C	p.Gly59Arg	missense_variant	3/6		XP_005258805.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
DHDH	ENST00000221403.7 linkuse as main transcript	c.511G>C	p.Gly171Arg	missense_variant	4/7	1	NM_014475.4	ENSP00000221403	P1
DHDH	ENST00000522614.5 linkuse as main transcript	c.511G>C	p.Gly171Arg	missense_variant	4/5	5		ENSP00000428672
DHDH	ENST00000523250.5 linkuse as main transcript	c.203-2847G>C		intron_variant		5		ENSP00000428935
DHDH	ENST00000520557.1 linkuse as main transcript	c.311G>C	p.Trp104Ser	missense_variant, NMD_transcript_variant	3/5	5		ENSP00000430360

Frequencies

GnomAD3 genomes

AF:

0.00000935

AC:

AN:

107000

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000205

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000253

AC:

AN:

158368

Hom.:

AF XY:

0.0000234

AC XY:

AN XY:

85380

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000476

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:

0.0000366

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000199

AC:

AN:

1458844

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

725784

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000207

Gnomad4 OTH exome

AF:

0.0000498

GnomAD4 genome

AF:

0.00000935

AC:

AN:

107000

Hom.:

Cov.:

AF XY:

0.0000196

AC XY:

AN XY:

50916

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000205

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.0000183

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

Aug 16, 2021

The c.511G>C (p.G171R) alteration is located in exon 4 (coding exon 4) of the DHDH gene. This alteration results from a G to C substitution at nucleotide position 511, causing the glycine (G) at amino acid position 171 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

Pathogenic

0.75

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.21

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.35

T;.

Eigen

Pathogenic

0.81

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.74

T;T

M_CAP

Benign

0.037

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Uncertain

-0.10

MutationAssessor

Pathogenic

4.1

H;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-7.4

D;D

REVEL

Pathogenic

0.73

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

1.0

D;.

Vest4

0.95

MutPred

0.81

Loss of helix (P = 0.0068);Loss of helix (P = 0.0068);

MVP

0.49

MPC

0.65

ClinPred

1.0

GERP RS

5.1

Varity_R

0.59

gMVP

0.94

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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