NM_016246.3:c.728T>G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016246.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD17B14	NM_016246.3	MANE Select	c.728T>G	p.Leu243Arg	missense	Exon 9 of 9	NP_057330.2	Q9BPX1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD17B14	ENST00000263278.9	TSL:1 MANE Select	c.728T>G	p.Leu243Arg	missense	Exon 9 of 9	ENSP00000263278.3	Q9BPX1
	HSD17B14	ENST00000867480.1		c.854T>G	p.Leu285Arg	missense	Exon 10 of 10	ENSP00000537539.1
	HSD17B14	ENST00000867481.1		c.737T>G	p.Leu246Arg	missense	Exon 9 of 9	ENSP00000537540.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000426 AC: 1 AN: 235010 AF XY: 0.00000785

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33404

American (AMR) AF: 0.00 AC: 0 AN: 43798

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25916

East Asian (EAS) AF: 0.00 AC: 0 AN: 39520

South Asian (SAS) AF: 0.00 AC: 0 AN: 85078

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52922

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.0000315 AC: 35 AN: 1109536

Other (OTH) AF: 0.0000166 AC: 1 AN: 60164

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000355 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000825 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.88	D
PhyloP100		5.4
MVP		0.95
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.96
Mutation Taster		=46/54	disease causing

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

Other links and lift over

dbSNP: rs749090139; hg19: chr19-49316517;