19-48939551-A-T

Variant names:

• chr19-48939551-A-T
• rs2037827530
• NM_014475.4:c.469A>T

Variant summary

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

The NM_014475.4(DHDH):​c.469A>T​(p.Asn157Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: DHDH NM_014475.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.220

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=0.11799511).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DHDH	NM_014475.4	c.469A>T	p.Asn157Tyr	missense_variant	Exon 4 of 7	ENST00000221403.7	NP_055290.1
DHDH	XM_017026598.2	c.220A>T	p.Asn74Tyr	missense_variant	Exon 4 of 7		XP_016882087.1
DHDH	XM_047438617.1	c.469A>T	p.Asn157Tyr	missense_variant	Exon 4 of 5		XP_047294573.1
DHDH	XM_005258748.5	c.133A>T	p.Asn45Tyr	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.469A>T	p.Asn157Tyr	missense_variant	Exon 4 of 7	1	NM_014475.4	ENSP00000221403.2
DHDH	ENST00000522614.5	c.469A>T	p.Asn157Tyr	missense_variant	Exon 4 of 5	5		ENSP00000428672.1
DHDH	ENST00000523250.5	c.203-2889A>T		intron_variant	Intron 2 of 4	5		ENSP00000428935.1
DHDH	ENST00000520557.1	n.269A>T		non_coding_transcript_exon_variant	Exon 3 of 5	5		ENSP00000430360.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461886 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727242

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

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

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 27, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.469A>T (p.N157Y) alteration is located in exon 4 (coding exon 4) of the DHDH gene. This alteration results from a A to T substitution at nucleotide position 469, causing the asparagine (N) at amino acid position 157 to be replaced by a tyrosine (Y). 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	0.19
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	6.4
DANN	Benign	0.88
DEOGEN2	Benign	0.061	T;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.0017	T
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;.
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.4	N;D
REVEL	Benign	0.067
Sift	Benign	0.035	D;T
Sift4G	Benign	0.069	T;D
Polyphen		0.024	B;.
Vest4		0.23
MutPred		0.51		Loss of solvent accessibility (P = 0.0193);Loss of solvent accessibility (P = 0.0193);
MVP		0.061
MPC		0.21
ClinPred		0.11	T
GERP RS		-9.5
Varity_R		0.053
gMVP		0.40

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: rs2037827530; hg19: chr19-49442808;