19-48834299-C-T

Variant names:

• chr19-48834299-C-T
• rs755193292
• NM_016246.3:c.187G>A

Variant summary

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

The NM_016246.3(HSD17B14):​c.187G>A​(p.Val63Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,461,690 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: HSD17B14 NM_016246.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.01

Genes affected

HSD17B14 (HGNC:23238): (hydroxysteroid 17-beta dehydrogenase 14) 17-beta-hydroxysteroid dehydrogenases, such as HSD17B14, are primarily involved in metabolism of steroids at the C17 position and also of other substrates, such as fatty acids, prostaglandins, and xenobiotics (Lukacik et al., 2007 [PubMed 17067289]).[supplied by OMIM, Jun 2009]

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, 0.819

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSD17B14	NM_016246.3	c.187G>A	p.Val63Met	missense_variant	Exon 3 of 9	ENST00000263278.9	NP_057330.2
HSD17B14	XM_005258969.5	c.187G>A	p.Val63Met	missense_variant	Exon 3 of 8		XP_005259026.1
HSD17B14	XM_047438897.1	c.187G>A	p.Val63Met	missense_variant	Exon 3 of 7		XP_047294853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSD17B14	ENST00000263278.9	c.187G>A	p.Val63Met	missense_variant	Exon 3 of 9	1	NM_016246.3	ENSP00000263278.3
HSD17B14	ENST00000599157.5	c.187G>A	p.Val63Met	missense_variant	Exon 3 of 8	3		ENSP00000472746.1
HSD17B14	ENST00000595764.1	c.79G>A	p.Val27Met	missense_variant	Exon 2 of 7	5		ENSP00000469557.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251332 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135840

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461690 Hom.: 0 Cov.: 30 AF XY: 0.00000963 AC XY: 7 AN XY: 727152

Gnomad4 AFR exome AF: 0.00

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: 0.00000989

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 31, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.187G>A (p.V63M) alteration is located in exon 3 (coding exon 3) of the HSD17B14 gene. This alteration results from a G to A substitution at nucleotide position 187, causing the valine (V) at amino acid position 63 to be replaced by a methionine (M). 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	0.33
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.028	T;.;D
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.061
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.82	D;D;D
MetaSVM	Uncertain	0.12	D
MutationAssessor	Uncertain	2.5	M;.;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-2.3	N;.;.
REVEL	Uncertain	0.51
Sift	Uncertain	0.026	D;.;.
Sift4G	Uncertain	0.032	D;D;D
Polyphen		0.99	D;.;.
Vest4		0.32
MutPred		0.71		Loss of catalytic residue at V63 (P = 0.1299);Loss of catalytic residue at V63 (P = 0.1299);.;
MVP		0.85
MPC		0.71
ClinPred		0.86	D
GERP RS		2.9
Varity_R		0.41
gMVP		0.64

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: rs755193292; hg19: chr19-49337556;