11-43854763-C-T

Variant names:

• chr11-43854763-C-T
• rs138665914
• NM_016142.3:c.733C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_016142.3(HSD17B12):​c.733C>T​(p.Pro245Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000149 in 1,614,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: HSD17B12 NM_016142.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.38
• Publications: 2 publications found

Genes affected

HSD17B12 (HGNC:18646): (hydroxysteroid 17-beta dehydrogenase 12) This gene encodes a very important 17beta-hydroxysteroid dehydrogenase (17beta-HSD) that converts estrone into estradiol in ovarian tissue. This enzyme is also involved in fatty acid elongation. [provided by RefSeq, Oct 2011]

ENSG00000246250 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05455336).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSD17B12	NM_016142.3	c.733C>T	p.Pro245Ser	missense_variant	Exon 10 of 11	ENST00000278353.10	NP_057226.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSD17B12	ENST00000278353.10	c.733C>T	p.Pro245Ser	missense_variant	Exon 10 of 11	1	NM_016142.3	ENSP00000278353.4

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000220

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000676 AC: 17 AN: 251468 AF XY: 0.0000662

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000149

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000153 AC: 224 AN: 1461858 Hom.: 0 Cov.: 30 AF XY: 0.000142 AC XY: 103 AN XY: 727236

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.000175 AC: 195 AN: 1111996

Other (OTH) AF: 0.000480 AC: 29 AN: 60392

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152292 Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7 AN XY: 74448

African (AFR) AF: 0.0000241 AC: 1 AN: 41578

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000220 AC: 15 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000165 Hom.: 0

Bravo AF: 0.0000869

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0000576 AC: 7

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.733C>T (p.P245S) alteration is located in exon 10 (coding exon 10) of the HSD17B12 gene. This alteration results from a C to T substitution at nucleotide position 733, causing the proline (P) at amino acid position 245 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.16	T;T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.60
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.055	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;.
PhyloP100		1.4
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.1	N;.
REVEL	Benign	0.070
Sift	Benign	0.43	T;.
Sift4G	Benign	0.52	T;.
Polyphen		0.026	B;.
Vest4		0.48
MVP		0.40
MPC		0.29
ClinPred		0.056	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.041
gMVP		0.59
Mutation Taster		=56/44	polymorphism

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: rs138665914; hg19: chr11-43876313;