16-30985761-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_025193.4(HSD3B7):c.103C>T(p.Arg35Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,452,574 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R35G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: HSD3B7 NM_025193.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4232488).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSD3B7	NM_025193.4	c.103C>T	p.Arg35Trp	missense_variant	2/7	ENST00000297679.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSD3B7	ENST00000297679.10	c.103C>T	p.Arg35Trp	missense_variant	2/7	1	NM_025193.4	P1
	ENST00000624286.1	n.2510G>A		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000218 AC: 5 AN: 229224 Hom.: 0 AF XY: 0.00000802 AC XY: 1 AN XY: 124762

Gnomad AFR exome AF: 0.0000718

Gnomad AMR exome AF: 0.0000307

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000575

Gnomad SAS exome AF: 0.0000349

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000977

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000186 AC: 27 AN: 1452574 Hom.: 0 Cov.: 33 AF XY: 0.0000194 AC XY: 14 AN XY: 721902

Gnomad4 AFR exome AF: 0.0000600

Gnomad4 AMR exome AF: 0.0000231

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0000472

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 20, 2023

The c.103C>T (p.R35W) alteration is located in exon 2 (coding exon 1) of the HSD3B7 gene. This alteration results from a C to T substitution at nucleotide position 103, causing the arginine (R) at amino acid position 35 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.084	T
BayesDel_noAF	Benign	-0.17
Cadd	Benign	22
Dann	Uncertain	1.0
Eigen	Benign	-0.041
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.32	N
LIST_S2	Uncertain	0.88	D;D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.42	T;T;T;T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	1.6	L;L;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.8	D;D;.;.
REVEL	Uncertain	0.43
Sift	Uncertain	0.0090	D;D;.;.
Sift4G	Uncertain	0.017	D;D;D;D
Polyphen		1.0	.;D;.;.
Vest4		0.46
MutPred		0.50		Loss of disorder (P = 0.0292);Loss of disorder (P = 0.0292);Loss of disorder (P = 0.0292);Loss of disorder (P = 0.0292);
MVP		0.90
MPC		0.78
ClinPred		0.33	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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;