19-48815050-T-C

Variant names:

• chr19-48815050-T-C
• NM_016246.3:c.461A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_016246.3(HSD17B14):​c.461A>G​(p.Tyr154Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,126 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: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HSD17B14 NM_016246.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.90

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a active_site Proton acceptor (size 0) in uniprot entity DHB14_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSD17B14	NM_016246.3	c.461A>G	p.Tyr154Cys	missense_variant	Exon 6 of 9	ENST00000263278.9	NP_057330.2
HSD17B14	XM_005258969.5	c.461A>G	p.Tyr154Cys	missense_variant	Exon 6 of 8		XP_005259026.1
HSD17B14	XM_047438897.1	c.369A>G	p.Leu123Leu	synonymous_variant	Exon 5 of 7		XP_047294853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSD17B14	ENST00000263278.9	c.461A>G	p.Tyr154Cys	missense_variant	Exon 6 of 9	1	NM_016246.3	ENSP00000263278.3
HSD17B14	ENST00000599157.5	c.389A>G	p.Tyr130Cys	missense_variant	Exon 5 of 8	3		ENSP00000472746.1
HSD17B14	ENST00000595764.1	c.353A>G	p.Tyr118Cys	missense_variant	Exon 5 of 7	5		ENSP00000469557.1
HSD17B14	ENST00000596349.5	c.23A>G	p.Tyr8Cys	missense_variant	Exon 1 of 4	5		ENSP00000471631.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461126 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726892

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.461A>G (p.Y154C) alteration is located in exon 6 (coding exon 6) of the HSD17B14 gene. This alteration results from a A to G substitution at nucleotide position 461, causing the tyrosine (Y) at amino acid position 154 to be replaced by a cysteine (C). 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	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T;.;.;D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-8.0	D;.;.;.
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;.;.;.
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.93
MutPred		0.87		Gain of catalytic residue at P153 (P = 0.0077);.;.;.;
MVP		0.98
MPC		1.0
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.97
gMVP		0.97

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: chr19-49318307;