chr16-30985702-CAG-C
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_025193.4(HSD3B7):c.45_46del(p.Gly17LeufsTer26) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000746 in 1,608,782 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000081 ( 0 hom. )
Consequence
HSD3B7
NM_025193.4 frameshift
NM_025193.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.97
Genes affected
HSD3B7 (HGNC:18324): (hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 7) This gene encodes an enzyme which is involved in the initial stages of the synthesis of bile acids from cholesterol and a member of the short-chain dehydrogenase/reductase superfamily. The encoded protein is a membrane-associated endoplasmic reticulum protein which is active against 7-alpha hydrosylated sterol substrates. Mutations in this gene are associated with a congenital bile acid synthesis defect which leads to neonatal cholestasis, a form of progressive liver disease. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 8 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 16-30985702-CAG-C is Pathogenic according to our data. Variant chr16-30985702-CAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 2885.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-30985702-CAG-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HSD3B7 | NM_025193.4 | c.45_46del | p.Gly17LeufsTer26 | frameshift_variant | 2/7 | ENST00000297679.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HSD3B7 | ENST00000297679.10 | c.45_46del | p.Gly17LeufsTer26 | frameshift_variant | 2/7 | 1 | NM_025193.4 | P1 | |
ENST00000624286.1 | n.2567_2568del | non_coding_transcript_exon_variant | 1/1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152270Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000372 AC: 9AN: 242084Hom.: 0 AF XY: 0.0000380 AC XY: 5AN XY: 131446
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GnomAD4 exome AF: 0.0000810 AC: 118AN: 1456512Hom.: 0 AF XY: 0.0000911 AC XY: 66AN XY: 724454
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152270Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74390
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Congenital bile acid synthesis defect 1 Pathogenic:3
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 2003 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | May 22, 2022 | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported to be associated with HSD3B7 related disorder (ClinVar ID: VCV000002885). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 16, 2022 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2022 | HSD3B7: PVS1, PM2, PM3 - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 27, 2017 | - - |
HSD3B7-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 26, 2023 | The HSD3B7 c.45_46delAG variant is predicted to result in a frameshift and premature protein termination (p.Gly17Leufs*26). This variant was reported in individuals with 3 beta-hydroxysteroid oxidoreductase deficiency or congenital bile acid synthesis defect (for example, see Cheng et al. 2003. PubMed ID: 12679481, reported as 63, ΔAG; Stalke et al. 2018. PubMed ID: 28776642). This variant is reported in 0.013% of alleles in individuals of African descent in gnomAD. Frameshift variants in HSD3B7 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at