16-30985793-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_025193.4(HSD3B7):c.135C>G(p.His45Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: HSD3B7 NM_025193.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.185

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12607849).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSD3B7	NM_025193.4	c.135C>G	p.His45Gln	missense_variant	2/7	ENST00000297679.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSD3B7	ENST00000297679.10	c.135C>G	p.His45Gln	missense_variant	2/7	1	NM_025193.4	P1
	ENST00000624286.1	n.2478G>C		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

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

Oct 02, 2023

The c.135C>G (p.H45Q) alteration is located in exon 2 (coding exon 1) of the HSD3B7 gene. This alteration results from a C to G substitution at nucleotide position 135, causing the histidine (H) at amino acid position 45 to be replaced by a glutamine (Q). 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	0.15
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	14
Dann	Benign	0.92
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.60	T;T;T;T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.13	T;T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.1	L;L;.;.
MutationTaster	Benign	0.51	D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.6	N;N;.;.
REVEL	Benign	0.13
Sift	Benign	0.67	T;T;.;.
Sift4G	Benign	0.59	T;T;T;T
Polyphen		0.042	.;B;.;.
Vest4		0.19
MutPred		0.47		Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);
MVP		0.63
MPC		0.28
ClinPred		0.12	T
GERP RS		0.49
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-30997114;