chr19-48944456-G-A

Variant names:

• chr19-48944456-G-A
• rs3765148
• NM_014475.4:c.844G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014475.4(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. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.074 (465 hom., cov: 32)
  • Exomes 𝑓: 0.062 (2935 hom.)
• Consequence: DHDH NM_014475.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.07
• Publications: 22 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014475.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHDH	NM_014475.4	MANE Select	c.844G>A	p.Gly282Arg	missense	Exon 6 of 7	NP_055290.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHDH	ENST00000221403.7	TSL:1 MANE Select	c.844G>A	p.Gly282Arg	missense	Exon 6 of 7	ENSP00000221403.2
	DHDH	ENST00000523250.5	TSL:5	c.427G>A	p.Gly143Arg	missense	Exon 4 of 5	ENSP00000428935.1
	DHDH	ENST00000520557.1	TSL:5	n.*105G>A		non_coding_transcript_exon	Exon 4 of 5	ENSP00000430360.1

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

GnomAD2 exomes AF: 0.0610 AC: 15327 AN: 251092 AF XY: 0.0603

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 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

African (AFR) AF: 0.107 AC: 3577 AN: 33478

American (AMR) AF: 0.0527 AC: 2356 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.0451 AC: 1177 AN: 26122

East Asian (EAS) AF: 0.0606 AC: 2406 AN: 39694

South Asian (SAS) AF: 0.0561 AC: 4839 AN: 86214

European-Finnish (FIN) AF: 0.0565 AC: 3017 AN: 53404

Middle Eastern (MID) AF: 0.0732 AC: 422 AN: 5766

European-Non Finnish (NFE) AF: 0.0620 AC: 68927 AN: 1111672

Other (OTH) AF: 0.0655 AC: 3952 AN: 60378

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

African (AFR) AF: 0.105 AC: 4367 AN: 41544

American (AMR) AF: 0.0610 AC: 932 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0493 AC: 171 AN: 3468

East Asian (EAS) AF: 0.0499 AC: 258 AN: 5174

South Asian (SAS) AF: 0.0542 AC: 262 AN: 4832

European-Finnish (FIN) AF: 0.0565 AC: 598 AN: 10590

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0641 AC: 4361 AN: 67994

Other (OTH) AF: 0.0752 AC: 159 AN: 2114

Alfa AF: 0.0666 Hom.: 1373

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 v4.9

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
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		1.1
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.080
Sift	Uncertain	0.026	D
Sift4G	Uncertain	0.0080	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
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

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