rs1555907623

Positions:

• chrX-11772246-CGATTGTTT-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_078629.4(MSL3):​c.1374_1381del​(p.Leu459GlufsTer13) variant causes a frameshift, splice region 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 NM_078629.4 frameshift, splice_region
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.87

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]

ACMG classification

Verdict is Pathogenic. Variant got 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 id is 487565.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSL3	NM_078629.4	c.1374_1381del	p.Leu459GlufsTer13	frameshift_variant, splice_region_variant	11/13	ENST00000312196.10
MSL3	NM_001193270.2	c.1338_1345del	p.Leu447GlufsTer13	frameshift_variant, splice_region_variant	11/13
MSL3	NM_001282174.1	c.927_934del	p.Leu310GlufsTer13	frameshift_variant, splice_region_variant	10/12
MSL3	NM_006800.4	c.876_883del	p.Leu293GlufsTer13	frameshift_variant, splice_region_variant	10/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSL3	ENST00000312196.10	c.1374_1381del	p.Leu459GlufsTer13	frameshift_variant, splice_region_variant	11/13	1	NM_078629.4	P4

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

Likely pathogenic, criteria provided, single submitter

research

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Jan 01, 2017

- -

Basilicata-Akhtar syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 12, 2019

- -

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: rs1555907623; hg19: chrX-11790365;