16-30987821-A-G

Variant names:

• chr16-30987821-A-G
• rs9938550
• NM_025193.4:c.748A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_025193.4(HSD3B7):​c.748A>G​(p.Thr250Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.602 in 1,612,980 control chromosomes in the GnomAD database, including 303,549 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 0.53 (23619 hom., cov: 34)
  • Exomes 𝑓: 0.61 (279930 hom.)
• Consequence: HSD3B7 NM_025193.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.602
• Publications: 59 publications found

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]

HSD3B7 Gene-Disease associations (from GenCC):

• congenital bile acid synthesis defect 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P, Labcorp Genetics (formerly Invitae)

ENSG00000279196 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.0653583E-7).
• BP6: Variant 16-30987821-A-G is Benign according to our data. Variant chr16-30987821-A-G is described in ClinVar as Benign. ClinVar VariationId is 261873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.884 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSD3B7	NM_025193.4	c.748A>G	p.Thr250Ala	missense_variant	Exon 7 of 7	ENST00000297679.10	NP_079469.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSD3B7	ENST00000297679.10	c.748A>G	p.Thr250Ala	missense_variant	Exon 7 of 7	1	NM_025193.4	ENSP00000297679.5
HSD3B7	ENST00000262520.10	c.585A>G	p.Gln195Gln	synonymous_variant	Exon 6 of 6	2		ENSP00000262520.6
ENSG00000279196	ENST00000624286.1	n.450T>C		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes AF: 0.530 AC: 80523 AN: 152056 Hom.: 23603 Cov.: 34

Gnomad AFR AF: 0.279

Gnomad AMI AF: 0.631

Gnomad AMR AF: 0.571

Gnomad ASJ AF: 0.690

Gnomad EAS AF: 0.905

Gnomad SAS AF: 0.308

Gnomad FIN AF: 0.668

Gnomad MID AF: 0.737

Gnomad NFE AF: 0.626

Gnomad OTH AF: 0.593

GnomAD2 exomes AF: 0.585 AC: 146027 AN: 249454 AF XY: 0.579

Gnomad AFR exome AF: 0.261

Gnomad AMR exome AF: 0.561

Gnomad ASJ exome AF: 0.673

Gnomad EAS exome AF: 0.911

Gnomad FIN exome AF: 0.657

Gnomad NFE exome AF: 0.634

Gnomad OTH exome AF: 0.609

GnomAD4 exome AF: 0.610 AC: 890708 AN: 1460806 Hom.: 279930 Cov.: 61 AF XY: 0.604 AC XY: 438775 AN XY: 726750

African (AFR) AF: 0.265 AC: 8878 AN: 33478

American (AMR) AF: 0.565 AC: 25254 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.673 AC: 17572 AN: 26128

East Asian (EAS) AF: 0.910 AC: 36122 AN: 39696

South Asian (SAS) AF: 0.332 AC: 28670 AN: 86254

European-Finnish (FIN) AF: 0.654 AC: 34315 AN: 52458

Middle Eastern (MID) AF: 0.699 AC: 4033 AN: 5766

European-Non Finnish (NFE) AF: 0.629 AC: 699076 AN: 1111922

Other (OTH) AF: 0.609 AC: 36788 AN: 60380

GnomAD4 genome AF: 0.530 AC: 80584 AN: 152174 Hom.: 23619 Cov.: 34 AF XY: 0.531 AC XY: 39478 AN XY: 74408

African (AFR) AF: 0.280 AC: 11616 AN: 41506

American (AMR) AF: 0.571 AC: 8728 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.690 AC: 2396 AN: 3470

East Asian (EAS) AF: 0.906 AC: 4679 AN: 5166

South Asian (SAS) AF: 0.310 AC: 1496 AN: 4826

European-Finnish (FIN) AF: 0.668 AC: 7088 AN: 10610

Middle Eastern (MID) AF: 0.741 AC: 218 AN: 294

European-Non Finnish (NFE) AF: 0.626 AC: 42544 AN: 67984

Other (OTH) AF: 0.590 AC: 1246 AN: 2112

Alfa AF: 0.595 Hom.: 42813

Bravo AF: 0.521

TwinsUK AF: 0.622 AC: 2306

ALSPAC AF: 0.628 AC: 2421

ESP6500AA AF: 0.289 AC: 1271

ESP6500EA AF: 0.642 AC: 5518

ExAC AF: 0.572 AC: 69382

Asia WGS AF: 0.547 AC: 1908 AN: 3478

EpiCase AF: 0.635

EpiControl AF: 0.644

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 28973304) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:2

Feb 25, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital bile acid synthesis defect 1 Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	6.4
DANN	Benign	0.51
DEOGEN2	Benign	0.23	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0075	N
LIST_S2	Benign	0.034	T
MetaRNN	Benign	9.1e-7	T
MetaSVM	Benign	-0.97	T
PhyloP100		-0.60
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.076
Sift	Benign	0.48	T
Sift4G	Benign	0.79	T
Polyphen		0.0	B
Vest4		0.0040
MPC		0.27
ClinPred		0.0092	T
GERP RS		0.28
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.037
gMVP		0.46
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs9938550; hg19: chr16-30999142; COSMIC: COSV52680147; COSMIC: COSV52680147;