chr17-42553802-T-C
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_000413.4(HSD17B1):c.454T>C(p.Phe152Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000093 in 1,612,990 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: 𝑓 0.000053 ( 0 hom., cov: 34)
Exomes 𝑓: 0.0000048 ( 0 hom. )
Consequence
HSD17B1
NM_000413.4 missense
NM_000413.4 missense
Scores
2
11
3
Clinical Significance
Conservation
PhyloP100: 4.82
Genes affected
HSD17B1 (HGNC:5210): (hydroxysteroid 17-beta dehydrogenase 1) This gene encodes a member of the 17beta-hydroxysteroid dehydrogenase family of short-chain dehydrogenases/reductases. It has a dual function in estrogen activation and androgen inactivation and plays a major role in establishing the estrogen E2 concentration gradient between serum and peripheral tissues. The encoded protein catalyzes the last step in estrogen activation, using NADPH to convert estrogens E1 and E2 and androgens like 4-androstenedione, to testosterone. It has an N-terminal short-chain dehydrogenase domain with a cofactor binding site, and a narrow, hydrophobic C-terminal domain with a steroid substrate binding site. This gene is expressed primarily in the placenta and ovarian granulosa cells, and to a lesser extent, in the endometrium, adipose tissue, and prostate. Polymorphisms in this gene have been linked to breast and prostate cancer. A pseudogene of this gene has been identified. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2016]
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ACMG classification
Classification made for transcript
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, 0.837
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HSD17B1 | NM_000413.4 | c.454T>C | p.Phe152Leu | missense_variant | 4/6 | ENST00000585807.6 | |
HSD17B1-AS1 | NR_144402.1 | n.1001A>G | non_coding_transcript_exon_variant | 1/1 | |||
HSD17B1 | NM_001330219.3 | c.454T>C | p.Phe152Leu | missense_variant | 4/6 | ||
HSD17B1 | NR_144397.2 | n.456+184T>C | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HSD17B1 | ENST00000585807.6 | c.454T>C | p.Phe152Leu | missense_variant | 4/6 | 1 | NM_000413.4 | P4 | |
HSD17B1-AS1 | ENST00000590513.3 | n.1040A>G | non_coding_transcript_exon_variant | 1/1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152174Hom.: 0 Cov.: 34
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GnomAD3 exomes AF: 0.0000241 AC: 6AN: 249106Hom.: 0 AF XY: 0.0000223 AC XY: 3AN XY: 134764
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GnomAD4 exome AF: 0.00000479 AC: 7AN: 1460816Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 726634
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GnomAD4 genome ? AF: 0.0000526 AC: 8AN: 152174Hom.: 0 Cov.: 34 AF XY: 0.0000807 AC XY: 6AN XY: 74346
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 31, 2023 | The c.454T>C (p.F152L) alteration is located in exon 4 (coding exon 4) of the HSD17B1 gene. This alteration results from a T to C substitution at nucleotide position 454, causing the phenylalanine (F) at amino acid position 152 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Uncertain
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Uncertain
D;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
N;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
Sift4G
Uncertain
D;D
Polyphen
D;.
Vest4
MutPred
Loss of catalytic residue at F152 (P = 0.1084);Loss of catalytic residue at F152 (P = 0.1084);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at