NM_004493.3:c.634A>G

Variant names:

• chrX-53431556-T-C
• rs886041974
• NM_004493.3:c.634A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP4

The NM_004493.3(HSD17B10):​c.634A>G​(p.Lys212Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. K212K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 22)
• Consequence: HSD17B10 NM_004493.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.78
• Publications: 4 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: 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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-53431556-T-C is Pathogenic according to our data. Variant chrX-53431556-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 280839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.36886364). . Strength limited to SUPPORTING due to the PP5.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD17B10	NM_004493.3	MANE Select	c.634A>G	p.Lys212Glu	missense	Exon 6 of 6	NP_004484.1
	HSD17B10	NM_001037811.2		c.607A>G	p.Lys203Glu	missense	Exon 6 of 6	NP_001032900.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD17B10	ENST00000168216.11	TSL:1 MANE Select	c.634A>G	p.Lys212Glu	missense	Exon 6 of 6	ENSP00000168216.6
	HSD17B10	ENST00000375304.9	TSL:1	c.607A>G	p.Lys203Glu	missense	Exon 6 of 6	ENSP00000364453.5
	HSD17B10	ENST00000477706.1	TSL:3	n.258A>G		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Dec 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

HSD17B10: PM1, PM2, PS3:Moderate, PS4:Supporting

Sep 15, 2016

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Introduction of the K212E variant into E. coli found that it is associated with significantly reduceddehydrogenase activity of the SDR5C1 enzyme compared to wild-type (Falk et al., 2016).Additional functional analysis found that the K212E variant also results in impaired 5' processingand methylation of mt-tRNAs (Falk et al., 2016). The K212E variant is located with the substratespecificity loop and is predicted to alter active site closure of the SDR5C1 enzyme (Falk et al.,2016). The K212E variant was not observed in approximately 6,500 individuals of European andAfrican American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a commonbenign variant in these populations. The K212E variant is a non-conservative amino acidsubstitution, which is likely to impact secondary protein structure as these residues differ inpolarity, charge, size and/or other properties. This substitution occurs at a position that isconserved across species. In silico analysis is inconsistent in its predictions as to whether or notthe variant is damaging to the protein structure/function. In summary, we interpret K212E to be apathogenic variant.

HSD10 mitochondrial disease Pathogenic:1

May 10, 2017

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.17
CADD	Benign	23
DANN	Benign	0.89
DEOGEN2	Benign	0.39	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.70	D
MetaRNN	Benign	0.37	T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	-0.47	N
PhyloP100		4.8
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.48
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.025	B
Vest4		0.44
MutPred		0.41		Loss of methylation at K212 (P = 0.0183)
MVP		0.99
MPC		4.2
ClinPred		0.78	D
GERP RS		5.9
Varity_R		0.74
gMVP		0.97
Mutation Taster		=5/95	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: rs886041974; hg19: chrX-53458504;