19-48939599-G-C

Variant names:

• chr19-48939599-G-C
• rs1006726849
• NM_014475.4:c.517G>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_014475.4(DHDH):​c.517G>C​(p.Ala173Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DHDH NM_014475.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.89

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.839

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DHDH	NM_014475.4	c.517G>C	p.Ala173Pro	missense_variant	Exon 4 of 7	ENST00000221403.7	NP_055290.1
DHDH	XM_017026598.2	c.268G>C	p.Ala90Pro	missense_variant	Exon 4 of 7		XP_016882087.1
DHDH	XM_047438617.1	c.517G>C	p.Ala173Pro	missense_variant	Exon 4 of 5		XP_047294573.1
DHDH	XM_005258748.5	c.181G>C	p.Ala61Pro	missense_variant	Exon 3 of 6		XP_005258805.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DHDH	ENST00000221403.7	c.517G>C	p.Ala173Pro	missense_variant	Exon 4 of 7	1	NM_014475.4	ENSP00000221403.2
DHDH	ENST00000522614.5	c.517G>C	p.Ala173Pro	missense_variant	Exon 4 of 5	5		ENSP00000428672.1
DHDH	ENST00000523250.5	c.203-2841G>C		intron_variant	Intron 2 of 4	5		ENSP00000428935.1
DHDH	ENST00000520557.1	n.317G>C		non_coding_transcript_exon_variant	Exon 3 of 5	5		ENSP00000430360.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251406 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135906

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: 6.84e-7 AC: 1 AN: 1461872 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Benign	-0.066	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T;.
Eigen	Benign	-0.076
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.54	T;T
M_CAP	Benign	0.0060	T
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.4	M;.
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-2.7	D;D
REVEL	Benign	0.24
Sift	Uncertain	0.027	D;D
Sift4G	Uncertain	0.051	T;D
Polyphen		0.94	P;.
Vest4		0.68
MutPred		0.70		Loss of helix (P = 0.0167);Loss of helix (P = 0.0167);
MVP		0.49
MPC		0.20
ClinPred		0.84	D
GERP RS		1.9
Varity_R		0.58
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1006726849; hg19: chr19-49442856;