16-30985665-G-A

Position:

• chr16-30985665-G-A

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.7G>A​(p.Asp3Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000604 in 1,604,800 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000098 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000056 (0 hom.)
• Consequence: HSD3B7 NM_025193.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.89

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=0.0039640367).
• BP6: Variant 16-30985665-G-A is Benign according to our data. Variant chr16-30985665-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 594048.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000984 (15/152366) while in subpopulation EAS AF= 0.0027 (14/5186). AF 95% confidence interval is 0.00163. There are 0 homozygotes in gnomad4. There are 5 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.7G>A	p.Asp3Asn	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.7G>A	p.Asp3Asn	missense_variant	2/7	1	NM_025193.4	ENSP00000297679	P1
	ENST00000624286.1	n.2606C>T		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.0000985 AC: 15 AN: 152248 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: 0.00269

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000235 AC: 56 AN: 238584 Hom.: 0 AF XY: 0.000193 AC XY: 25 AN XY: 129434

Gnomad AFR exome AF: 0.0000655

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00288

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000919

Gnomad OTH exome AF: 0.000342

GnomAD4 exome AF: 0.0000565 AC: 82 AN: 1452434 Hom.: 0 Cov.: 33 AF XY: 0.0000568 AC XY: 41 AN XY: 722370

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00134

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.000399

GnomAD4 genome AF: 0.0000984 AC: 15 AN: 152366 Hom.: 0 Cov.: 33 AF XY: 0.0000671 AC XY: 5 AN XY: 74504

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00270

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000138 Hom.: 0

Bravo AF: 0.000132

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000272 AC: 33

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 18, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.091	.;T;T;.
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.67	T;T;T;T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.0040	T;T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.55	N;N;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.61	N;N;.;.
REVEL	Benign	0.11
Sift	Benign	0.47	T;T;.;.
Sift4G	Uncertain	0.025	D;D;D;D
Polyphen		0.0	.;B;.;.
Vest4		0.13
MVP		0.75
MPC		0.27
ClinPred		0.023	T
GERP RS		2.6
Varity_R		0.051
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs200555135; hg19: chr16-30996986;