NM_014475.4:c.31G>A

Variant names:

• chr19-48933752-G-A
• NM_014475.4:c.31G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_014475.4(DHDH):​c.31G>A​(p.Gly11Ser) variant causes a missense change. 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: 32)
• Consequence: DHDH NM_014475.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.83

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_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DHDH	NM_014475.4	c.31G>A	p.Gly11Ser	missense_variant	Exon 1 of 7	ENST00000221403.7	NP_055290.1
DHDH	XM_047438617.1	c.31G>A	p.Gly11Ser	missense_variant	Exon 1 of 5		XP_047294573.1
DHDH	XM_017026598.2	c.-160+272G>A		intron_variant	Intron 1 of 6		XP_016882087.1
DHDH	XM_005258748.5	c.-83+272G>A		intron_variant	Intron 1 of 5		XP_005258805.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DHDH	ENST00000221403.7	c.31G>A	p.Gly11Ser	missense_variant	Exon 1 of 7	1	NM_014475.4	ENSP00000221403.2
DHDH	ENST00000522614.5	c.31G>A	p.Gly11Ser	missense_variant	Exon 1 of 5	5		ENSP00000428672.1
DHDH	ENST00000523250.5	c.31G>A	p.Gly11Ser	missense_variant	Exon 1 of 5	5		ENSP00000428935.1
DHDH	ENST00000520557.1	n.-6G>A		upstream_gene_variant		5		ENSP00000430360.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 21, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.31G>A (p.G11S) alteration is located in exon 1 (coding exon 1) of the DHDH gene. This alteration results from a G to A substitution at nucleotide position 31, causing the glycine (G) at amino acid position 11 to be replaced by a serine (S). 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	0.54
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T;.;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Benign	0.067	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Uncertain	2.2	M;.;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-5.4	D;D;D
REVEL	Uncertain	0.58
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.010	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.85
MutPred		0.84		Gain of MoRF binding (P = 0.0815);Gain of MoRF binding (P = 0.0815);Gain of MoRF binding (P = 0.0815);
MVP		0.62
MPC		0.59
ClinPred		0.99	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.88
gMVP		0.92

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-49437009;