NM_000862.3:c.382G>T

Variant names:

• chr1-119513905-G-T
• rs1333585891
• NM_000862.3:c.382G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000862.3(HSD3B1):​c.382G>T​(p.Val128Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. V128I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HSD3B1 NM_000862.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.16

Genes affected

HSD3B1 (HGNC:5217): (hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 1) The protein encoded by this gene is an enzyme that catalyzes the oxidative conversion of delta-5-3-beta-hydroxysteroid precursors into delta-4-ketosteroids, which leads to the production of all classes of steroid hormones. The encoded protein also catalyzes the interconversion of 3-beta-hydroxy- and 3-keto-5-alpha-androstane steroids. [provided by RefSeq, Jun 2016]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.952

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSD3B1	NM_000862.3	c.382G>T	p.Val128Leu	missense_variant	Exon 4 of 4	ENST00000369413.8	NP_000853.1
HSD3B1	NM_001328615.1	c.382G>T	p.Val128Leu	missense_variant	Exon 4 of 4		NP_001315544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSD3B1	ENST00000369413.8	c.382G>T	p.Val128Leu	missense_variant	Exon 4 of 4	1	NM_000862.3	ENSP00000358421.3
HSD3B1	ENST00000528909.1	c.382G>T	p.Val128Leu	missense_variant	Exon 3 of 3	1		ENSP00000432268.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251138 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135712

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461816 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727208

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.13
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.74	D;D
Eigen	Benign	0.083
Eigen_PC	Benign	-0.037
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.74	.;T
M_CAP	Benign	0.065	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Pathogenic	4.5	H;H
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.017	D;D
Sift4G	Uncertain	0.035	D;D
Polyphen		0.13	B;B
Vest4		0.86
MVP		0.80
MPC		0.058
ClinPred		0.83	D
GERP RS		2.8
Varity_R		0.66
gMVP		0.65

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: rs1333585891; hg19: chr1-120056528;