X-53431484-G-A

Position:

• chrX-53431484-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP5_Moderate

The NM_004493.3(HSD17B10):​c.706C>T​(p.Leu236Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. L236L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 22)
• Consequence: HSD17B10 NM_004493.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.99

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a chain 3-hydroxyacyl-CoA dehydrogenase type-2 (size 259) in uniprot entity HCD2_HUMAN there are 20 pathogenic changes around while only 6 benign (77%) in NM_004493.3
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-53431484-G-A is Pathogenic according to our data. Variant chrX-53431484-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2502293.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSD17B10	NM_004493.3	c.706C>T	p.Leu236Phe	missense_variant	6/6	ENST00000168216.11
HSD17B10	NM_001037811.2	c.679C>T	p.Leu227Phe	missense_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSD17B10	ENST00000168216.11	c.706C>T	p.Leu236Phe	missense_variant	6/6	1	NM_004493.3	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

HSD10 mitochondrial disease Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Inherited Metabolic Diseases, Karolinska University Hospital

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	.;T
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Uncertain	0.74	D;D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Uncertain	2.4	.;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.5	D;D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.53
MutPred		0.58		.;Gain of catalytic residue at Q238 (P = 0.1356);
MVP		0.94
MPC		3.0
ClinPred		0.99	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.95
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-53458432;