19-48939482-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014475.4(DHDH):c.400G>A(p.Ala134Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: DHDH NM_014475.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.14

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09244275).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DHDH	NM_014475.4	c.400G>A	p.Ala134Thr	missense_variant	4/7	ENST00000221403.7
DHDH	XM_017026598.2	c.151G>A	p.Ala51Thr	missense_variant	4/7
DHDH	XM_047438617.1	c.400G>A	p.Ala134Thr	missense_variant	4/5
DHDH	XM_005258748.5	c.64G>A	p.Ala22Thr	missense_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DHDH	ENST00000221403.7	c.400G>A	p.Ala134Thr	missense_variant	4/7	1	NM_014475.4	P1
DHDH	ENST00000522614.5	c.400G>A	p.Ala134Thr	missense_variant	4/5	5
DHDH	ENST00000523250.5	c.203-2958G>A		intron_variant		5
DHDH	ENST00000520557.1	c.200G>A	p.Gly67Asp	missense_variant, NMD_transcript_variant	3/5	5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

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

Jul 12, 2022

The c.400G>A (p.A134T) alteration is located in exon 4 (coding exon 4) of the DHDH gene. This alteration results from a G to A substitution at nucleotide position 400, causing the alanine (A) at amino acid position 134 to be replaced by a threonine (T). 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	Benign	0.084
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	18
Dann	Uncertain	0.98
DEOGEN2	Benign	0.021	T;.
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.71	T;T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.092	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;.
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.39	N;N
REVEL	Benign	0.085
Sift	Benign	0.41	T;T
Sift4G	Benign	0.40	T;T
Polyphen		0.038	B;.
Vest4		0.066
MutPred		0.35		Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);
MVP		0.20
MPC		0.12
ClinPred		0.24	T
GERP RS		1.4
Varity_R		0.043
gMVP		0.20

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-49442739;