X-53432381-G-C

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1BP4_ModerateBS2

The NM_004493.3(HSD17B10):c.223C>G(p.Leu75Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000935 in 1,208,058 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 31 hemizygotes in GnomAD. 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000063 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.000097 ( 0 hom. 29 hem. )

Consequence

HSD17B10
NM_004493.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.244

Variant links:

Genes affected

HSD17B10 (HGNC:4800): (hydroxysteroid 17-beta dehydrogenase 10) This gene encodes 3-hydroxyacyl-CoA dehydrogenase type II, a member of the short-chain dehydrogenase/reductase superfamily. The gene product is a mitochondrial protein that catalyzes the oxidation of a wide variety of fatty acids and steroids, and is a subunit of mitochondrial ribonuclease P, which is involved in tRNA maturation. The protein has been implicated in the development of Alzheimer disease, and mutations in the gene are the cause of 17beta-hydroxysteroid dehydrogenase type 10 (HSD10) deficiency. Several alternatively spliced transcript variants have been identified, but the full-length nature of only two transcript variants has been determined. [provided by RefSeq, Aug 2014]

HSD17B10 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM1

In a chain 3-hydroxyacyl-CoA dehydrogenase type-2 (size 259) in uniprot entity HCD2_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_004493.3

BP4

Computational evidence support a benign effect (MetaRNN=0.09775916).

BS2

High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSD17B10	NM_004493.3 link	c.223C>G	p.Leu75Val	missense_variant	Exon 3 of 6	ENST00000168216.11	NP_004484.1	Q99714-1A0A0S2Z410
HSD17B10	NM_001037811.2 link	c.223C>G	p.Leu75Val	missense_variant	Exon 3 of 6		NP_001032900.1	Q99714-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSD17B10	ENST00000168216.11 link	c.223C>G	p.Leu75Val	missense_variant	Exon 3 of 6	1	NM_004493.3	ENSP00000168216.6		Q99714-1

Frequencies

GnomAD3 genomes

AF:

0.0000626

AC:

AN:

111736

Hom.:

Cov.:

AF XY:

0.0000590

AC XY:

AN XY:

33914

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000493

AC:

AN:

182501

Hom.:

AF XY:

0.0000447

AC XY:

AN XY:

67079

show subpopulations

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000977

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.0000967

AC:

106

AN:

1096322

Hom.:

Cov.:

AF XY:

0.0000801

AC XY:

AN XY:

361924

show subpopulations

Gnomad4 AFR exome

AF:

0.0000379

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000115

Gnomad4 OTH exome

AF:

0.000174

GnomAD4 genome

AF:

0.0000626

AC:

AN:

111736

Hom.:

Cov.:

AF XY:

0.0000590

AC XY:

AN XY:

33914

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

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:

0.00

Bravo

AF:

0.0000869

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000297

AC:

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 26, 2017

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:1

Dec 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 75 of the HSD17B10 protein (p.Leu75Val). This variant is present in population databases (rs374438347, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with HSD17B10-related conditions. ClinVar contains an entry for this variant (Variation ID: 435471). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt HSD17B10 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.45

CADD

Benign

7.3

DANN

Benign

0.70

DEOGEN2

Benign

0.40

.;T;T

FATHMM_MKL

Benign

0.76

LIST_S2

Uncertain

0.93

D;D;D

M_CAP

Benign

0.064

MetaRNN

Benign

0.098

T;T;T

MetaSVM

Benign

-0.72

MutationAssessor

Benign

-0.95

N;N;.

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.5

N;N;N

REVEL

Benign

0.28

Sift

Benign

0.72

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0010

B;B;.

Vest4

0.28

MVP

0.65

MPC

0.51

ClinPred

0.021

GERP RS

4.2

Varity_R

0.39

gMVP

0.87

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over