16-30985702-CAG-C

Variant names:

• chr16-30985702-CAG-C
• rs786200876
• NM_025193.4:c.45_46delAG

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 5.97
• Publications: 7 publications found

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, Labcorp Genetics (formerly Invitae), G2P

ENSG00000279196 (HGNC:):

ACMG classification

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 VariationId is 2885.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025193.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD3B7	NM_025193.4	MANE Select	c.45_46delAG	p.Gly17LeufsTer26	frameshift	Exon 2 of 7	NP_079469.2
	HSD3B7	NM_001142777.2		c.45_46delAG	p.Gly17LeufsTer26	frameshift	Exon 2 of 6	NP_001136249.1	Q9H2F3-2
	HSD3B7	NM_001142778.2		c.45_46delAG	p.Gly17LeufsTer26	frameshift	Exon 2 of 6	NP_001136250.1	Q9H2F3-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD3B7	ENST00000297679.10	TSL:1 MANE Select	c.45_46delAG	p.Gly17LeufsTer26	frameshift	Exon 2 of 7	ENSP00000297679.5	Q9H2F3-1
	HSD3B7	ENST00000867909.1		c.45_46delAG	p.Gly17LeufsTer26	frameshift	Exon 2 of 7	ENSP00000537968.1
	HSD3B7	ENST00000867910.1		c.45_46delAG	p.Gly17LeufsTer26	frameshift	Exon 2 of 7	ENSP00000537969.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152270 Hom.: 0 Cov.: 33

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

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

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

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152270 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74390

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

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000529

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Congenital bile acid synthesis defect 1 (5)
2	-	-	not provided (2)
1	-	-	Congenital bile acid synthesis defect (1)
1	-	-	HSD3B7-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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

Other links and lift over

dbSNP: rs786200876; hg19: chr16-30997023;