19-48939467-T-G

Variant names:

• chr19-48939467-T-G
• NM_014475.4:c.385T>G

Variant summary

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

The NM_014475.4(DHDH):​c.385T>G​(p.Phe129Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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: 7.21

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, 0.762

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DHDH	NM_014475.4	c.385T>G	p.Phe129Val	missense_variant	Exon 4 of 7	ENST00000221403.7	NP_055290.1
DHDH	XM_017026598.2	c.136T>G	p.Phe46Val	missense_variant	Exon 4 of 7		XP_016882087.1
DHDH	XM_047438617.1	c.385T>G	p.Phe129Val	missense_variant	Exon 4 of 5		XP_047294573.1
DHDH	XM_005258748.5	c.49T>G	p.Phe17Val	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.385T>G	p.Phe129Val	missense_variant	Exon 4 of 7	1	NM_014475.4	ENSP00000221403.2
DHDH	ENST00000522614.5	c.385T>G	p.Phe129Val	missense_variant	Exon 4 of 5	5		ENSP00000428672.1
DHDH	ENST00000523250.5	c.203-2973T>G		intron_variant	Intron 2 of 4	5		ENSP00000428935.1
DHDH	ENST00000520557.1	n.185T>G		non_coding_transcript_exon_variant	Exon 3 of 5	5		ENSP00000430360.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 14, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.385T>G (p.F129V) alteration is located in exon 4 (coding exon 4) of the DHDH gene. This alteration results from a T to G substitution at nucleotide position 385, causing the phenylalanine (F) at amino acid position 129 to be replaced by a valine (V). 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	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T;.
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.012	T
MetaRNN	Pathogenic	0.76	D;D
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.7	M;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-6.8	D;D
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.85
MutPred		0.55		Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);
MVP		0.33
MPC		0.57
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.71

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-49442724;