rs1064794694

chrX-53432035-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_004493.3(HSD17B10):c.439C>T(p.Arg147Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: HSD17B10 NM_004493.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 1.51

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 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
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.916
• PP5: Variant X-53432035-G-A is Pathogenic according to our data. Variant chrX-53432035-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 420778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-53432035-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSD17B10	NM_004493.3	c.439C>T	p.Arg147Cys	missense_variant	4/6	ENST00000168216.11
HSD17B10	NM_001037811.2	c.439C>T	p.Arg147Cys	missense_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSD17B10	ENST00000168216.11	c.439C>T	p.Arg147Cys	missense_variant	4/6	1	NM_004493.3	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

HSD10 mitochondrial disease Pathogenic:2 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Oct 18, 2021	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Pathogenic and reported on 10-28-2020 by Lab or GTR ID UCLA Molecular Diagnostics Laboratory. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Breda Genetics srl	Jul 20, 2021	The variant c.439C>T (p.Arg147Cys) in the HSD17B10 gene, rs1064794694, reference transcript NM_001037811.2 is reported as likely pathogenic for a congenital disease in ClinVar (Variation ID: 420778) and in Global Variome shared LOVD 3.0 (genomic variant: #0000576627). There is no information on frequency in gnomAD. The nucleotide position is highly conserved across 35 mammalian species (GERP RS:5.81). In silico analysis indicates that the variant might be damaging. -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	HSD17B10: PM2, PM6, PS4:Moderate, PP2 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 22, 2022	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12555940, 15342248, 34765396) -

Neurodevelopmental delay Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

-

- -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 26, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
Cadd	Pathogenic	30
Dann	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Uncertain	2.5	M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-7.6	D;D;D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0080	D;D;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		0.99	D;D;.
Vest4		0.73
MutPred		0.63		Loss of disorder (P = 0.0246);Loss of disorder (P = 0.0246);Loss of disorder (P = 0.0246);
MVP		1.0
MPC		4.1
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.93
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1064794694; hg19: chrX-53458983;