16-30988113-T-G

Variant names:

• chr16-30988113-T-G
• rs34212827
• NM_025193.4:c.1040T>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The ENST00000297679.10(HSD3B7):​c.1040T>G​(p.Leu347Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,972 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L347P) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: HSD3B7 ENST00000297679.10 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.94
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000297679.10. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD3B7	NM_025193.4	MANE Select	c.1040T>G	p.Leu347Arg	missense	Exon 7 of 7	NP_079469.2
	HSD3B7	NM_001142777.2		c.*286T>G		3_prime_UTR	Exon 6 of 6	NP_001136249.1
	HSD3B7	NM_001142778.2		c.*286T>G		3_prime_UTR	Exon 6 of 6	NP_001136250.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD3B7	ENST00000297679.10	TSL:1 MANE Select	c.1040T>G	p.Leu347Arg	missense	Exon 7 of 7	ENSP00000297679.5
	ENSG00000279196	ENST00000624286.1	TSL:6	n.158A>C		non_coding_transcript_exon	Exon 1 of 1
	HSD3B7	ENST00000262520.10	TSL:2	c.*286T>G		3_prime_UTR	Exon 6 of 6	ENSP00000262520.6

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453972 Hom.: 0 Cov.: 64 AF XY: 0.00000138 AC XY: 1 AN XY: 723118

African (AFR) AF: 0.00 AC: 0 AN: 33412

American (AMR) AF: 0.00 AC: 0 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39642

South Asian (SAS) AF: 0.00 AC: 0 AN: 86192

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1110324

Other (OTH) AF: 0.00 AC: 0 AN: 60262

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	0.0071	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.60	T
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	1.7	L
PhyloP100		1.9
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-3.9	D
REVEL	Benign	0.22
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.075	T
Polyphen		0.78	P
Vest4		0.21
MutPred		0.41		Gain of disorder (P = 0.0128)
MVP		0.77
MPC		0.92
ClinPred		0.98	D
GERP RS		5.2
Varity_R		0.75
gMVP		0.91

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

Other links and lift over

dbSNP: rs34212827; hg19: chr16-30999434;