rs28935476

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 6P and 4B. PM1PP3_StrongBS2

The NM_004493.3(HSD17B10):c.364C>G(p.Leu122Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,209,658 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L122L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000046 ( 0 hom. 3 hem. )

Consequence

HSD17B10
NM_004493.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 1.00

Publications

17 publications found

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 Gene-Disease associations (from GenCC):

HSD10 mitochondrial disease
Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen
HSD10 disease, infantile type
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
HSD10 disease, neonatal type
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
syndromic X-linked intellectual disability type 10
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

HSD17B10 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_004493.3

PP3

MetaRNN computational evidence supports a deleterious effect, 0.948

BS2

High Hemizygotes in GnomAdExome4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSD17B10	NM_004493.3 link	c.364C>G	p.Leu122Val	missense_variant	Exon 4 of 6	ENST00000168216.11	NP_004484.1
HSD17B10	NM_001037811.2 link	c.364C>G	p.Leu122Val	missense_variant	Exon 4 of 6		NP_001032900.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSD17B10	ENST00000168216.11 link	c.364C>G	p.Leu122Val	missense_variant	Exon 4 of 6	1	NM_004493.3	ENSP00000168216.6

Frequencies

GnomAD3 genomes

AF:

0.00000896

AC:

AN:

111583

Hom.:

Cov.:

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:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000545

AC:

AN:

183335

AF XY:

0.0000148

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000455

AC:

AN:

1098075

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

363431

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26400

American (AMR)

AF:

0.00

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19384

East Asian (EAS)

AF:

0.00

AC:

AN:

30205

South Asian (SAS)

AF:

0.00

AC:

AN:

54145

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40481

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4134

European-Non Finnish (NFE)

AF:

0.00000475

AC:

AN:

842023

Other (OTH)

AF:

0.0000217

AC:

AN:

46096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000896

AC:

AN:

111583

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33765

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30667

American (AMR)

AF:

0.00

AC:

AN:

10532

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2648

East Asian (EAS)

AF:

0.00

AC:

AN:

3555

South Asian (SAS)

AF:

0.00

AC:

AN:

2652

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6019

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53085

Other (OTH)

AF:

0.00

AC:

AN:

1503

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

HSD10 mitochondrial disease

Pathogenic:1

May 01, 2003

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not specified

Uncertain:1

Feb 01, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: HSD17B10 c.364C>G (p.Leu122Val) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5e-06 in 1209658 control chromosomes in the gnomAD database, including 3 hemizygotes. c.364C>G has been reported in the literature in a male patient affected with 2-methyl-3-hydroxybutyryl-CoA dehydrogenase (MHBD) deficiency (Ofman_2003, Poll-The_2004). In addition, the variant has also been reported in ten individuals from four unrelated French-Canadian families: two asymptomatic male individuals, four asymptomatic female individuals and one female with mild intellectual deficiency and speech difficulty, one male affected with spastic paraplegia and dysarthria who had a reportedly pathogenic de novo variant in SPAST which could account for his phenotype, one male with dystonic episodes which gradually diminished without treatment, and one female affected with developmental delay and axial hypotonia who had a co-occurring pathogenic variant in CACNA1A resulting in a diagnosis of episodic ataxia (Waters_2019). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function and found the variant did not affect protein expression, but resulted in 2-3 % of normal MHBD activity in vitro (Ofman_2003). The following publications have been ascertained in the context of this evaluation (PMID: 12696021, 16148061, 15059617, 31654490). ClinVar contains an entry for this variant (Variation ID: 11443). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.24

.;T;T

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.97

D;D;D

M_CAP

Pathogenic

0.50

MetaRNN

Pathogenic

0.95

D;D;D

MetaSVM

Uncertain

-0.20

MutationAssessor

Benign

0.19

N;N;.

PhyloP100

1.0

PrimateAI

Benign

0.44

PROVEAN

Benign

0.12

N;N;N

REVEL

Uncertain

0.46

Sift

Benign

0.13

T;T;T

Sift4G

Benign

0.13

T;T;T

Polyphen

0.0020

B;B;.

Vest4

0.55

MutPred

0.84

Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);

MVP

1.0

MPC

0.46

ClinPred

0.19

GERP RS

4.9

Varity_R

0.39

gMVP

0.87

Mutation Taster

=85/15

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over