NM_025193.4:c.45_46delAG

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_025193.4(HSD3B7):​c.45_46delAG​(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

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 5.97

Publications

7 publications found
Variant links:
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]
HSD3B7 Gene-Disease associations (from GenCC):
  • congenital bile acid synthesis defect 1
    Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P, Labcorp Genetics (formerly Invitae)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 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 19 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.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HSD3B7NM_025193.4 linkc.45_46delAG p.Gly17LeufsTer26 frameshift_variant Exon 2 of 7 ENST00000297679.10 NP_079469.2 Q9H2F3-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HSD3B7ENST00000297679.10 linkc.45_46delAG p.Gly17LeufsTer26 frameshift_variant Exon 2 of 7 1 NM_025193.4 ENSP00000297679.5 Q9H2F3-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152270
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000372
AC:
9
AN:
242084
AF XY:
0.0000380
show subpopulations
Gnomad AFR exome
AF:
0.000128
Gnomad AMR exome
AF:
0.0000293
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000548
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000458
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000810
AC:
118
AN:
1456512
Hom.:
0
AF XY:
0.0000911
AC XY:
66
AN XY:
724454
show subpopulations
African (AFR)
AF:
0.0000599
AC:
2
AN:
33398
American (AMR)
AF:
0.0000225
AC:
1
AN:
44484
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26034
East Asian (EAS)
AF:
0.0000756
AC:
3
AN:
39686
South Asian (SAS)
AF:
0.00
AC:
0
AN:
85596
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
51396
Middle Eastern (MID)
AF:
0.000229
AC:
1
AN:
4374
European-Non Finnish (NFE)
AF:
0.0000972
AC:
108
AN:
1111384
Other (OTH)
AF:
0.0000499
AC:
3
AN:
60160
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.482
Heterozygous variant carriers
0
9
17
26
34
43
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
10
20
30
40
50
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152270
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74390
show subpopulations
African (AFR)
AF:
0.0000241
AC:
1
AN:
41470
American (AMR)
AF:
0.00
AC:
0
AN:
15292
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5202
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4834
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10628
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68052
Other (OTH)
AF:
0.00
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.500
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.000142
Hom.:
0
Bravo
AF:
0.0000529

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Congenital bile acid synthesis defect 1 Pathogenic:5
Feb 16, 2022
Fulgent Genetics, Fulgent Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Mar 06, 2024
3billion
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). Predicted Consequence/Location: 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 at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000002885 /PMID: 12679481, 28776642 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Nov 11, 2024
Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Apr 01, 2003
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

-
Juno Genomics, Hangzhou Juno Genomics, Inc
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

PVS1+PM2_Supporting+PM3_Strong+PP4 -

not provided Pathogenic:2
Jun 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

HSD3B7: PVS1, PM2, PM3 -

Sep 27, 2017
Eurofins Ntd Llc (ga)
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

HSD3B7-related disorder Pathogenic:1
Dec 26, 2023
PreventionGenetics, part of Exact Sciences
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing

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. -

Congenital bile acid synthesis defect Pathogenic:1
Oct 04, 2024
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:research

PVS1(strong),PM2, PM3 moderate -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
6.0
Mutation Taster
=2/198
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs786200876; hg19: chr16-30997023; API