11-43754106-G-T

Variant summary

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

The NM_016142.3(HSD17B12):c.268G>T(p.Val90Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: HSD17B12 NM_016142.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.47

Genes affected

HSD17B12 (HGNC:18646): (hydroxysteroid 17-beta dehydrogenase 12) This gene encodes a very important 17beta-hydroxysteroid dehydrogenase (17beta-HSD) that converts estrone into estradiol in ovarian tissue. This enzyme is also involved in fatty acid elongation. [provided by RefSeq, Oct 2011]

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, 0.867

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSD17B12	NM_016142.3	c.268G>T	p.Val90Phe	missense_variant	3/11	ENST00000278353.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSD17B12	ENST00000278353.10	c.268G>T	p.Val90Phe	missense_variant	3/11	1	NM_016142.3	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 30, 2023

The c.268G>T (p.V90F) alteration is located in exon 3 (coding exon 3) of the HSD17B12 gene. This alteration results from a G to T substitution at nucleotide position 268, causing the valine (V) at amino acid position 90 to be replaced by a phenylalanine (F). 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	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D;.;T;T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.88	D;D;D;T
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.87	D;D;D;D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Uncertain	2.0	M;M;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.9	D;D;.;.
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0010	D;D;.;.
Sift4G	Uncertain	0.0020	D;D;.;.
Polyphen		1.0	D;.;.;.
Vest4		0.65
MutPred		0.69		Loss of MoRF binding (P = 0.0842);Loss of MoRF binding (P = 0.0842);Loss of MoRF binding (P = 0.0842);.;
MVP		0.93
MPC		1.1
ClinPred		0.98	D
GERP RS		4.5
Varity_R		0.66
gMVP		0.95

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: chr11-43775656;