X-53432108-GAG-CAC

Variant names:

• chrX-53432108-GAG-CAC
• NM_004493.3:c.364_366delCTCinsGTG
• HSD17B10 p.Leu122Val

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM1

The NM_004493.3(HSD17B10):​c.364_366delCTCinsGTG​(p.Leu122Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. L122L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 22)
• Consequence: HSD17B10 NM_004493.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.11
• Publications: 0 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, Labcorp Genetics (formerly Invitae), G2P
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_004493.3

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.364_366delCTCinsGTG	p.Leu122Val	missense	N/A	NP_004484.1	A0A0S2Z410
	HSD17B10	NM_001037811.2		c.364_366delCTCinsGTG	p.Leu122Val	missense	N/A	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.364_366delCTCinsGTG	p.Leu122Val	missense	N/A	ENSP00000168216.6	Q99714-1
	HSD17B10	ENST00000375304.9	TSL:1	c.364_366delCTCinsGTG	p.Leu122Val	missense	N/A	ENSP00000364453.5	Q99714-2
	HSD17B10	ENST00000868389.1		c.349_351delCTCinsGTG	p.Leu117Val	missense	N/A	ENSP00000538448.1

Frequencies

GnomAD3 genomes Cov.: 22

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.1

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chrX-53459056;