chr19-48944456-G-A

Position:

• chr19-48944456-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000221403.7(DHDH):​c.844G>A​(p.Gly282Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0631 in 1,613,616 control chromosomes in the GnomAD database, including 3,400 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.074 (465 hom., cov: 32)
  • Exomes 𝑓: 0.062 (2935 hom.)
• Consequence: DHDH ENST00000221403.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.07

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0024238825).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.103 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DHDH	NM_014475.4	c.844G>A	p.Gly282Arg	missense_variant	6/7	ENST00000221403.7	NP_055290.1
DHDH	XM_017026598.2	c.595G>A	p.Gly199Arg	missense_variant	6/7		XP_016882087.1
DHDH	XM_005258748.5	c.508G>A	p.Gly170Arg	missense_variant	5/6		XP_005258805.1
DHDH	XM_047438617.1	c.*47G>A		3_prime_UTR_variant	5/5		XP_047294573.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DHDH	ENST00000221403.7	c.844G>A	p.Gly282Arg	missense_variant	6/7	1	NM_014475.4	ENSP00000221403	P1
DHDH	ENST00000523250.5	c.427G>A	p.Gly143Arg	missense_variant	4/5	5		ENSP00000428935
DHDH	ENST00000522614.5	c.620-368G>A		intron_variant		5		ENSP00000428672
DHDH	ENST00000520557.1	c.*105G>A		3_prime_UTR_variant, NMD_transcript_variant	4/5	5		ENSP00000430360

Frequencies

GnomAD3 genomes AF: 0.0738 AC: 11218 AN: 152086 Hom.: 463 Cov.: 32

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.0611

Gnomad ASJ AF: 0.0493

Gnomad EAS AF: 0.0496

Gnomad SAS AF: 0.0546

Gnomad FIN AF: 0.0565

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0641

Gnomad OTH AF: 0.0760

GnomAD3 exomes AF: 0.0610 AC: 15327 AN: 251092 Hom.: 499 AF XY: 0.0603 AC XY: 8188 AN XY: 135694

Gnomad AFR exome AF: 0.108

Gnomad AMR exome AF: 0.0525

Gnomad ASJ exome AF: 0.0437

Gnomad EAS exome AF: 0.0516

Gnomad SAS exome AF: 0.0565

Gnomad FIN exome AF: 0.0561

Gnomad NFE exome AF: 0.0620

Gnomad OTH exome AF: 0.0635

GnomAD4 exome AF: 0.0620 AC: 90673 AN: 1461412 Hom.: 2935 Cov.: 31 AF XY: 0.0619 AC XY: 44987 AN XY: 726980

Gnomad4 AFR exome AF: 0.107

Gnomad4 AMR exome AF: 0.0527

Gnomad4 ASJ exome AF: 0.0451

Gnomad4 EAS exome AF: 0.0606

Gnomad4 SAS exome AF: 0.0561

Gnomad4 FIN exome AF: 0.0565

Gnomad4 NFE exome AF: 0.0620

Gnomad4 OTH exome AF: 0.0655

GnomAD4 genome AF: 0.0737 AC: 11224 AN: 152204 Hom.: 465 Cov.: 32 AF XY: 0.0731 AC XY: 5437 AN XY: 74426

Gnomad4 AFR AF: 0.105

Gnomad4 AMR AF: 0.0610

Gnomad4 ASJ AF: 0.0493

Gnomad4 EAS AF: 0.0499

Gnomad4 SAS AF: 0.0542

Gnomad4 FIN AF: 0.0565

Gnomad4 NFE AF: 0.0641

Gnomad4 OTH AF: 0.0752

Alfa AF: 0.0648 Hom.: 905

Bravo AF: 0.0761

TwinsUK AF: 0.0502 AC: 186

ALSPAC AF: 0.0688 AC: 265

ESP6500AA AF: 0.103 AC: 456

ESP6500EA AF: 0.0605 AC: 520

ExAC AF: 0.0627 AC: 7614

Asia WGS AF: 0.0570 AC: 199 AN: 3478

EpiCase AF: 0.0658

EpiControl AF: 0.0632

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.040	T;.
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.67	T;T
MetaRNN	Benign	0.0024	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.9	N;N
REVEL	Benign	0.080
Sift	Uncertain	0.026	D;D
Sift4G	Uncertain	0.0080	D;D
Polyphen		1.0	D;.
Vest4		0.21
MutPred		0.23		Gain of solvent accessibility (P = 0.0789);.;
MPC		0.62
ClinPred		0.032	T
GERP RS		0.086
Varity_R		0.082
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

Other links and lift over

dbSNP: rs3765148; hg19: chr19-49447713; COSMIC: COSV55482098;