chr16-30987929-G-A

Position:

• chr16-30987929-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_025193.4(HSD3B7):​c.856G>A​(p.Ala286Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0014 in 1,613,314 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0072 (8 hom., cov: 34)
  • Exomes 𝑓: 0.00079 (15 hom.)
• Consequence: HSD3B7 NM_025193.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0580

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=0.0023674667).
• BP6: Variant 16-30987929-G-A is Benign according to our data. Variant chr16-30987929-G-A is described in ClinVar as [Benign]. Clinvar id is 261875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-30987929-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00719 (1096/152330) while in subpopulation AFR AF= 0.0248 (1030/41564). AF 95% confidence interval is 0.0235. There are 8 homozygotes in gnomad4. There are 533 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSD3B7	NM_025193.4	c.856G>A	p.Ala286Thr	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.856G>A	p.Ala286Thr	missense_variant	7/7	1	NM_025193.4	ENSP00000297679.5
HSD3B7	ENST00000262520.10	c.*102G>A		3_prime_UTR_variant	6/6	2		ENSP00000262520.6
ENSG00000279196	ENST00000624286.1	n.342C>T		non_coding_transcript_exon_variant	1/1	6

Frequencies

GnomAD3 genomes AF: 0.00719 AC: 1095 AN: 152212 Hom.: 8 Cov.: 34

Gnomad AFR AF: 0.0248

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00169 AC: 422 AN: 249966 Hom.: 3 AF XY: 0.00124 AC XY: 168 AN XY: 135382

Gnomad AFR exome AF: 0.0238

Gnomad AMR exome AF: 0.000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000791 AC: 1156 AN: 1460984 Hom.: 15 Cov.: 65 AF XY: 0.000660 AC XY: 480 AN XY: 726862

Gnomad4 AFR exome AF: 0.0273

Gnomad4 AMR exome AF: 0.000805

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000107

Gnomad4 OTH exome AF: 0.00139

GnomAD4 genome AF: 0.00719 AC: 1096 AN: 152330 Hom.: 8 Cov.: 34 AF XY: 0.00715 AC XY: 533 AN XY: 74494

Gnomad4 AFR AF: 0.0248

Gnomad4 AMR AF: 0.00340

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00343 Hom.: 3

Bravo AF: 0.00875

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0247 AC: 108

ESP6500EA AF: 0.000234 AC: 2

ExAC AF: 0.00211 AC: 256

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 27, 2023	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	1.2
DANN	Benign	0.75
DEOGEN2	Benign	0.044	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0069	N
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.47	N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.43	N
REVEL	Benign	0.16
Sift	Benign	0.73	T
Sift4G	Benign	0.52	T
Polyphen		0.0010	B
Vest4		0.022
MVP		0.40
MPC		0.26
ClinPred		0.0054	T
GERP RS		-6.3
Varity_R		0.022
gMVP		0.26

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: rs76878398; hg19: chr16-30999250; COSMIC: COSV99034595; COSMIC: COSV99034595;