19-48935022-A-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014475.4(DHDH):c.113A>C(p.Asp38Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000642 in 1,576,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00067 (0 hom.)
• Consequence: DHDH NM_014475.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.33

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06529322).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DHDH	NM_014475.4	c.113A>C	p.Asp38Ala	missense_variant	2/7	ENST00000221403.7
DHDH	XM_047438617.1	c.113A>C	p.Asp38Ala	missense_variant	2/5
DHDH	XM_005258748.5	c.-60A>C		5_prime_UTR_variant	2/6
DHDH	XM_017026598.2	c.-137A>C		5_prime_UTR_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DHDH	ENST00000221403.7	c.113A>C	p.Asp38Ala	missense_variant	2/7	1	NM_014475.4	P1
DHDH	ENST00000522614.5	c.113A>C	p.Asp38Ala	missense_variant	2/5	5
DHDH	ENST00000523250.5	c.113A>C	p.Asp38Ala	missense_variant	2/5	5
DHDH	ENST00000520557.1	c.77A>C	p.Asp26Ala	missense_variant, NMD_transcript_variant	2/5	5

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 59 AN: 152068 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000691

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000366 AC: 74 AN: 201926 Hom.: 0 AF XY: 0.000293 AC XY: 32 AN XY: 109148

Gnomad AFR exome AF: 0.000165

Gnomad AMR exome AF: 0.000213

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000627

Gnomad NFE exome AF: 0.000695

Gnomad OTH exome AF: 0.000202

GnomAD4 exome AF: 0.000669 AC: 953 AN: 1424508 Hom.: 0 Cov.: 30 AF XY: 0.000636 AC XY: 449 AN XY: 705746

Gnomad4 AFR exome AF: 0.000123

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000816

Gnomad4 NFE exome AF: 0.000817

Gnomad4 OTH exome AF: 0.000711

GnomAD4 genome AF: 0.000388 AC: 59 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23 AN XY: 74410

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.000691

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000494 Hom.: 0

Bravo AF: 0.000363

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000466 AC: 4

ExAC AF: 0.000190 AC: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 19, 2022

The c.113A>C (p.D38A) alteration is located in exon 2 (coding exon 2) of the DHDH gene. This alteration results from a A to C substitution at nucleotide position 113, causing the aspartic acid (D) at amino acid position 38 to be replaced by an alanine (A). 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	Uncertain	0.39
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.40
Cadd	Uncertain	24
Dann	Benign	0.81
DEOGEN2	Benign	0.057	T;.;.
Eigen	Benign	0.031
Eigen_PC	Benign	0.12
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.85	T;D;D
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.065	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;.;.
MutationTaster	Benign	0.99	D;D;N
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-2.6	D;D;D
REVEL	Benign	0.19
Sift	Benign	0.13	T;T;T
Sift4G	Benign	0.51	T;T;T
Polyphen		0.18	B;.;.
Vest4		0.34
MVP		0.31
MPC		0.31
ClinPred		0.037	T
GERP RS		5.0
Varity_R		0.27
gMVP		0.50

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

Other links and lift over

dbSNP: rs200821290; hg19: chr19-49438279;