X-53432086-G-A

Variant names:

• chrX-53432086-G-A
• rs28935475
• NM_004493.3:c.388C>T

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3 PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_004493.3(HSD17B10):​c.388C>T​(p.Arg130Cys) variant causes a missense change involving the alteration of a 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 Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001244963: "immunoanalysis and studies of enzyme activity showed decreased amount of the enzyme and complete absence of enzyme activity (Yang S.Y., et al. (2009))"" and additional evidence is available in ClinVar.

• Frequency: Genomes: not found (cov: 23)
• Consequence: HSD17B10 NM_004493.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.32
• Publications: 34 publications found

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: ClinGen, G2P, Labcorp Genetics (formerly Invitae)
• 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

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001244963: "immunoanalysis and studies of enzyme activity showed decreased amount of the enzyme and complete absence of enzyme activity (Yang S.Y., et al. (2009))"; SCV006581279: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 12696021, 20077426).; SCV001396232: This variant has been reported to affect HSD17B10 protein function (PMID: 12696021, 24549042).
• 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
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant X-53432086-G-A is Pathogenic according to our data. Variant chrX-53432086-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 11442.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004493.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD17B10	NM_004493.3	MANE Select	c.388C>T	p.Arg130Cys	missense	Exon 4 of 6	NP_004484.1	A0A0S2Z410
	HSD17B10	NM_001037811.2		c.388C>T	p.Arg130Cys	missense	Exon 4 of 6	NP_001032900.1	Q99714-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD17B10	ENST00000168216.11	TSL:1 MANE Select	c.388C>T	p.Arg130Cys	missense	Exon 4 of 6	ENSP00000168216.6	Q99714-1
	HSD17B10	ENST00000375304.9	TSL:1	c.388C>T	p.Arg130Cys	missense	Exon 4 of 6	ENSP00000364453.5	Q99714-2
	HSD17B10	ENST00000868389.1		c.373C>T	p.Arg125Cys	missense	Exon 4 of 6	ENSP00000538448.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	HSD10 mitochondrial disease (4)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.85	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.5	M
PhyloP100		7.3
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-7.3	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.87		Gain of catalytic residue at R130 (P = 0.0814)
MVP		1.0
MPC		4.1
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.99
Mutation Taster		=2/98	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs28935475; hg19: chrX-53459034;