rs34212827

Positions:

• chr16-30988113-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_025193.4(HSD3B7):​c.1040T>C​(p.Leu347Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0218 in 1,606,266 control chromosomes in the GnomAD database, including 3,536 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.090 (1864 hom., cov: 34)
  • Exomes 𝑓: 0.015 (1672 hom.)
• Consequence: HSD3B7 NM_025193.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.94

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]

ENSG00000279196 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014500916).
• BP6: Variant 16-30988113-T-C is Benign according to our data. Variant chr16-30988113-T-C is described in ClinVar as [Benign]. Clinvar id is 261869.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-30988113-T-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.293 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSD3B7	NM_025193.4	c.1040T>C	p.Leu347Pro	missense_variant	7/7	ENST00000297679.10	NP_079469.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSD3B7	ENST00000297679.10	c.1040T>C	p.Leu347Pro	missense_variant	7/7	1	NM_025193.4	ENSP00000297679.5
HSD3B7	ENST00000262520.10	c.*286T>C		3_prime_UTR_variant	6/6	2		ENSP00000262520.6
ENSG00000279196	ENST00000624286.1	n.158A>G		non_coding_transcript_exon_variant	1/1	6

Frequencies

GnomAD3 genomes AF: 0.0900 AC: 13695 AN: 152194 Hom.: 1858 Cov.: 34

Gnomad AFR AF: 0.298

Gnomad AMI AF: 0.0462

Gnomad AMR AF: 0.0392

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00538

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.00760

Gnomad OTH AF: 0.0664

GnomAD3 exomes AF: 0.0281 AC: 6886 AN: 245154 Hom.: 763 AF XY: 0.0218 AC XY: 2902 AN XY: 133068

Gnomad AFR exome AF: 0.308

Gnomad AMR exome AF: 0.0203

Gnomad ASJ exome AF: 0.00728

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00701

Gnomad FIN exome AF: 0.000767

Gnomad NFE exome AF: 0.00741

Gnomad OTH exome AF: 0.0176

GnomAD4 exome AF: 0.0147 AC: 21374 AN: 1453954 Hom.: 1672 Cov.: 64 AF XY: 0.0137 AC XY: 9877 AN XY: 723110

Gnomad4 AFR exome AF: 0.306

Gnomad4 AMR exome AF: 0.0224

Gnomad4 ASJ exome AF: 0.00797

Gnomad4 EAS exome AF: 0.0000757

Gnomad4 SAS exome AF: 0.00675

Gnomad4 FIN exome AF: 0.000819

Gnomad4 NFE exome AF: 0.00688

Gnomad4 OTH exome AF: 0.0249

GnomAD4 genome AF: 0.0901 AC: 13717 AN: 152312 Hom.: 1864 Cov.: 34 AF XY: 0.0867 AC XY: 6455 AN XY: 74488

Gnomad4 AFR AF: 0.297

Gnomad4 AMR AF: 0.0391

Gnomad4 ASJ AF: 0.00548

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00559

Gnomad4 FIN AF: 0.000753

Gnomad4 NFE AF: 0.00760

Gnomad4 OTH AF: 0.0658

Alfa AF: 0.0181 Hom.: 378

Bravo AF: 0.103

TwinsUK AF: 0.00674 AC: 25

ALSPAC AF: 0.00778 AC: 30

ESP6500AA AF: 0.289 AC: 1271

ESP6500EA AF: 0.00953 AC: 82

ExAC AF: 0.0331 AC: 4012

Asia WGS AF: 0.0290 AC: 101 AN: 3478

EpiCase AF: 0.00938

EpiControl AF: 0.0106

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 08, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.48	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Benign	0.23
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.99	D
Vest4		0.24
MPC		1.1
ClinPred		0.034	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.78
gMVP		0.97

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

LitVar

Other links and lift over

dbSNP: rs34212827; hg19: chr16-30999434;