16-30985761-C-G

Position:

• chr16-30985761-C-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_025193.4(HSD3B7):​c.103C>G​(p.Arg35Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000494 in 1,604,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00027 (0 hom.)
• Consequence: HSD3B7 NM_025193.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.0620

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.009693742).
• BP6: Variant 16-30985761-C-G is Benign according to our data. Variant chr16-30985761-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 195382.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00262 (399/152346) while in subpopulation AFR AF= 0.00883 (367/41578). AF 95% confidence interval is 0.00808. There are 0 homozygotes in gnomad4. There are 197 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSD3B7	NM_025193.4	c.103C>G	p.Arg35Gly	missense_variant	2/7	ENST00000297679.10	NP_079469.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSD3B7	ENST00000297679.10	c.103C>G	p.Arg35Gly	missense_variant	2/7	1	NM_025193.4	ENSP00000297679	P1
	ENST00000624286.1	n.2510G>C		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.00259 AC: 394 AN: 152228 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00873

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000654 AC: 150 AN: 229224 Hom.: 0 AF XY: 0.000505 AC XY: 63 AN XY: 124762

Gnomad AFR exome AF: 0.00897

Gnomad AMR exome AF: 0.000399

Gnomad ASJ exome AF: 0.000629

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000105

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000293

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000271 AC: 394 AN: 1452576 Hom.: 0 Cov.: 33 AF XY: 0.000242 AC XY: 175 AN XY: 721902

Gnomad4 AFR exome AF: 0.00920

Gnomad4 AMR exome AF: 0.000554

Gnomad4 ASJ exome AF: 0.000309

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0000945

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.000684

GnomAD4 genome AF: 0.00262 AC: 399 AN: 152346 Hom.: 0 Cov.: 33 AF XY: 0.00264 AC XY: 197 AN XY: 74496

Gnomad4 AFR AF: 0.00883

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000228 Hom.: 0

Bravo AF: 0.00301

ESP6500AA AF: 0.00661 AC: 29

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000767 AC: 93

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 09, 2023	BS1 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 06, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	HSD3B7: BS1 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Nov 24, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	.;T;T;.
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.67	T;T;T;T
MetaRNN	Benign	0.0097	T;T;T;T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	1.0	L;L;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.5	N;N;.;.
REVEL	Uncertain	0.33
Sift	Benign	0.29	T;T;.;.
Sift4G	Benign	0.38	T;T;T;T
Polyphen		0.54	.;P;.;.
Vest4		0.26
MVP		0.81
MPC		0.45
ClinPred		0.0097	T
GERP RS		2.8
Varity_R		0.10
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs150464212; hg19: chr16-30997082;