19-48813260-A-C

Variant names:

• chr19-48813260-A-C
• rs749090139
• NM_016246.3:c.728T>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_016246.3(HSD17B14):​c.728T>G​(p.Leu243Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000247 in 1,456,078 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: 0.000025 (0 hom.)
• Consequence: HSD17B14 NM_016246.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.42

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.883

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSD17B14	NM_016246.3	c.728T>G	p.Leu243Arg	missense_variant	Exon 9 of 9	ENST00000263278.9	NP_057330.2
HSD17B14	XM_005258969.5	c.631T>G	p.Cys211Gly	missense_variant	Exon 8 of 8		XP_005259026.1
HSD17B14	XM_047438897.1	c.*320T>G		downstream_gene_variant			XP_047294853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSD17B14	ENST00000263278.9	c.728T>G	p.Leu243Arg	missense_variant	Exon 9 of 9	1	NM_016246.3	ENSP00000263278.3
HSD17B14	ENST00000599157.5	c.656T>G	p.Leu219Arg	missense_variant	Exon 8 of 8	3		ENSP00000472746.1
HSD17B14	ENST00000595764.1	c.523T>G	p.Cys175Gly	missense_variant	Exon 7 of 7	5		ENSP00000469557.1
HSD17B14	ENST00000596349.5	c.313T>G	p.Cys105Gly	missense_variant	Exon 4 of 4	5		ENSP00000471631.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000426 AC: 1 AN: 235010 Hom.: 0 AF XY: 0.00000785 AC XY: 1 AN XY: 127400

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: 0.00000951

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000247 AC: 36 AN: 1456078 Hom.: 0 Cov.: 32 AF XY: 0.0000290 AC XY: 21 AN XY: 723748

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: 0.0000315

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000355 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000825 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.728T>G (p.L243R) alteration is located in exon 9 (coding exon 9) of the HSD17B14 gene. This alteration results from a T to G substitution at nucleotide position 728, causing the leucine (L) at amino acid position 243 to be replaced by an arginine (R). 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	0.84
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0054	.;T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.21	T;T
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.88	D;D
MVP		0.95
ClinPred		0.99	D
GERP RS		4.3

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: rs749090139; hg19: chr19-49316517;