rs1057516037

Positions:

• chrX-72464625-CTGGAG-CAC

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM4_Supporting PP3 PP5_Moderate

The NM_018486.3(HDAC8):​c.839_843delCTCCAinsGT​(p.Thr280_Pro281delinsSer) variant causes a missense, disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: HDAC8 NM_018486.3 missense, disruptive_inframe_deletion
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.37

Genes affected

HDAC8 (HGNC:13315): (histone deacetylase 8) Histones play a critical role in transcriptional regulation, cell cycle progression, and developmental events. Histone acetylation/deacetylation alters chromosome structure and affects transcription factor access to DNA. The protein encoded by this gene belongs to class I of the histone deacetylase family. It catalyzes the deacetylation of lysine residues in the histone N-terminal tails and represses transcription in large multiprotein complexes with transcriptional co-repressors. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]

ENSG00000285547 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_018486.3. Strenght limited to Supporting due to length of the change: 1aa.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant X-72464626-TGGAG-AC is Pathogenic according to our data. Variant chrX-72464626-TGGAG-AC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 369669.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HDAC8	NM_018486.3	c.839_843delCTCCAinsGT	p.Thr280_Pro281delinsSer	missense_variant, disruptive_inframe_deletion		ENST00000373573.9	NP_060956.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HDAC8	ENST00000373573.9	c.839_843delCTCCAinsGT	p.Thr280_Pro281delinsSer	missense_variant, disruptive_inframe_deletion		1	NM_018486.3	ENSP00000362674.3
ENSG00000285547	ENST00000648922.1	c.839_843delCTCCAinsGT	p.Thr280_Pro281delinsSer	missense_variant, disruptive_inframe_deletion				ENSP00000497072.1

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

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cornelia de Lange syndrome 5 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Feb 13, 2015

This deletion of 5 residues and insertion of two residues is predicted to result in a substitution of threonine for a serine at position 280, and a deletion of a proline at position 281. The amino acids at these positions are highly conserved. MutationTaster predicts this deletion to be deleterirous. Both amino acids are located in teh histone deacetylase domain in close proximity to the active site. This varaint is novel, and was found to be de novo on parental testing. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1057516037; hg19: chrX-71684476;