rs371014686

Positions:

chrX-53432345-C-T

Variant summary

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

The NM_004493.3(HSD17B10):c.259G>A(p.Val87Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000811 in 1,208,262 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 24 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000098 ( 0 hom., 3 hem., cov: 23)

Exomes 𝑓: 0.000079 ( 0 hom. 21 hem. )

Consequence

HSD17B10
NM_004493.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 0.952

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 19 pathogenic changes around while only 6 benign (76%) in NM_004493.3

BP4

Computational evidence support a benign effect (MetaRNN=0.17573792).

BS2

High Hemizygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSD17B10	NM_004493.3 linkuse as main transcript	c.259G>A	p.Val87Ile	missense_variant	3/6	ENST00000168216.11
HSD17B10	NM_001037811.2 linkuse as main transcript	c.259G>A	p.Val87Ile	missense_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSD17B10	ENST00000168216.11 linkuse as main transcript	c.259G>A	p.Val87Ile	missense_variant	3/6	1	NM_004493.3	P1	Q99714-1

Frequencies

GnomAD3 genomes

AF:

0.0000983

AC:

AN:

111900

Hom.:

Cov.:

AF XY:

0.0000881

AC XY:

AN XY:

34058

show subpopulations

Gnomad AFR

AF:

0.0000650

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:

0.000169

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000437

AC:

AN:

183269

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

67707

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000365

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:

0.0000854

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000794

AC:

AN:

1096362

Hom.:

Cov.:

AF XY:

0.0000580

AC XY:

AN XY:

361762

show subpopulations

Gnomad4 AFR exome

AF:

0.0000379

Gnomad4 AMR exome

AF:

0.0000284

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000495

Gnomad4 NFE exome

AF:

0.0000975

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

AF:

0.0000983

AC:

AN:

111900

Hom.:

Cov.:

AF XY:

0.0000881

AC XY:

AN XY:

34058

show subpopulations

Gnomad4 AFR

AF:

0.0000650

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:

0.000169

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000214

Hom.:

Bravo

AF:

0.0000907

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000692

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 13, 2016

- -

HSD10 mitochondrial disease

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 01, 2022

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 06, 2022

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 87 of the HSD17B10 protein (p.Val87Ile). This variant is present in population databases (rs371014686, gnomAD 0.01%). 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: 435470). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 15, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Benign

0.84

DEOGEN2

Benign

0.26

.;T;T

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.93

D;D;D

M_CAP

Pathogenic

0.53

MetaRNN

Benign

0.18

T;T;T

MetaSVM

Benign

-0.68

MutationAssessor

Benign

-0.17

N;N;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.67

N;N;N

REVEL

Uncertain

0.29

Sift

Benign

0.90

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

B;B;.

Vest4

0.17

MVP

0.59

MPC

0.38

ClinPred

0.16

GERP RS

5.1

Varity_R

0.14

gMVP

0.55

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