rs1057516037

Variant names:

• chrX-72464626-TGGAG-AC
• rs1057516037
• NM_018486.3:c.839_843delCTCCAinsGT

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 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
• Publications: 0 publications found

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]

HDAC8 Gene-Disease associations (from GenCC):

• Cornelia de Lange syndrome

  Inheritance: XL, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Cornelia de Lange syndrome 5

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• Wilson-Turner syndrome

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000285547 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_018486.3
• 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 VariationId is 369669.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018486.3. 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
	HDAC8	NM_018486.3	MANE Select	c.839_843delCTCCAinsGT	p.Thr280_Pro281delinsSer	missense disruptive_inframe_deletion	N/A	NP_060956.1	Q9BY41-1
	HDAC8	NM_001410725.1		c.839_843delCTCCAinsGT	p.Thr280_Pro281delinsSer	missense disruptive_inframe_deletion	N/A	NP_001397654.1	A0A3B3IS68
	HDAC8	NM_001410727.1		c.761_765delCTCCAinsGT	p.Thr254_Pro255delinsSer	missense disruptive_inframe_deletion	N/A	NP_001397656.1	A6NFW1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HDAC8	ENST00000373573.9	TSL:1 MANE Select	c.839_843delCTCCAinsGT	p.Thr280_Pro281delinsSer	missense disruptive_inframe_deletion	N/A	ENSP00000362674.3	Q9BY41-1
	ENSG00000285547	ENST00000648922.1		c.839_843delCTCCAinsGT	p.Thr280_Pro281delinsSer	missense disruptive_inframe_deletion	N/A	ENSP00000497072.1	A0A3B3IRV1
	HDAC8	ENST00000373568.7	TSL:5	c.839_843delCTCCAinsGT	p.Thr280_Pro281delinsSer	missense disruptive_inframe_deletion	N/A	ENSP00000362669.3	A6NGJ7

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

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Cornelia de Lange syndrome 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.4
Mutation Taster		=2/198	disease causing

Splicing

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

Other links and lift over

dbSNP: rs1057516037; hg19: chrX-71684476;