chrX-11772246-CGATTGTTT-C

Variant names:

• chrX-11772246-CGATTGTTT-C
• rs1555907623
• ENST00000312196.10:c.1349_1356delATTGTTTG

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The ENST00000312196.10(MSL3):​c.1349_1356delATTGTTTG​(p.Ile450GlufsTer13) variant causes a frameshift 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 (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 22)
• Consequence: MSL3 ENST00000312196.10 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.87
• Publications: 1 publications found

Genes affected

MSL3 (HGNC:7370): (MSL complex subunit 3) This gene encodes a nuclear protein that is similar to the product of the Drosophila male-specific lethal-3 gene. The Drosophila protein plays a critical role in a dosage-compensation pathway, which equalizes X-linked gene expression in males and females. Thus, the human protein is thought to play a similar function in chromatin remodeling and transcriptional regulation, and it has been found as part of a complex that is responsible for histone H4 lysine-16 acetylation. This gene can undergo X inactivation. Alternative splicing results in multiple transcript variants. Related pseudogenes have been identified on chromosomes 2, 7 and 8. [provided by RefSeq, Jul 2010]

MSL3 Gene-Disease associations (from GenCC):

• Basilicata-Akhtar syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, G2P

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-11772246-CGATTGTTT-C is Pathogenic according to our data. Variant chrX-11772246-CGATTGTTT-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 487565.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSL3	NM_078629.4	c.1374_1381delATTGTTTG	p.Leu459GlufsTer13	frameshift_variant, splice_region_variant	Exon 11 of 13	ENST00000312196.10	NP_523353.2
MSL3	NM_001193270.2	c.1338_1345delATTGTTTG	p.Leu447GlufsTer13	frameshift_variant, splice_region_variant	Exon 11 of 13		NP_001180199.1
MSL3	NM_001282174.1	c.927_934delATTGTTTG	p.Leu310GlufsTer13	frameshift_variant, splice_region_variant	Exon 10 of 12		NP_001269103.1
MSL3	NM_006800.4	c.876_883delATTGTTTG	p.Leu293GlufsTer13	frameshift_variant, splice_region_variant	Exon 10 of 12		NP_006791.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSL3	ENST00000312196.10	c.1349_1356delATTGTTTG	p.Ile450GlufsTer13	frameshift_variant	Exon 11 of 13	1	NM_078629.4	ENSP00000312244.4

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:2

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability Pathogenic:1

Jan 01, 2017

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Basilicata-Akhtar syndrome Pathogenic:1

Dec 12, 2019

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.9
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1555907623; hg19: chrX-11790365;