rs2147244798

Variant names:

• chrX-11762834-CAGTT-C
• rs2147244798
• NM_078629.4:c.590_593delTAGT

Variant summary

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

The ENST00000312196.10(MSL3):​c.589-2_590delAGTT​(p.Leu197fs) variant causes a frameshift, splice acceptor, splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 24)
• Consequence: MSL3 ENST00000312196.10 frameshift, splice_acceptor, splice_region, intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.60
• 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: G2P, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)

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-11762834-CAGTT-C is Pathogenic according to our data. Variant chrX-11762834-CAGTT-C is described in ClinVar as Pathogenic. ClinVar VariationId is 1700027.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000312196.10. 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
	MSL3	NM_078629.4	MANE Select	c.590_593delTAGT	p.Leu197fs	frameshift splice_region	Exon 7 of 13	NP_523353.2	Q8N5Y2-1
	MSL3	NM_001193270.2		c.554_557delTAGT	p.Leu185fs	frameshift splice_region	Exon 7 of 13	NP_001180199.1	Q8N5Y2-3
	MSL3	NM_078628.2		c.590_593delTAGT	p.Leu197fs	frameshift splice_region	Exon 7 of 9	NP_523352.1	Q8N5Y2-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSL3	ENST00000312196.10	TSL:1 MANE Select	c.589-2_590delAGTT	p.Leu197fs	frameshift splice_acceptor splice_region intron	Exon 7 of 13	ENSP00000312244.4	Q8N5Y2-1
	MSL3	ENST00000647869.1		c.589-2_590delAGTT	p.Leu197fs	frameshift splice_acceptor splice_region intron	Exon 7 of 13	ENSP00000497615.1	A0A3B3IT59
	MSL3	ENST00000398527.7	TSL:2	c.553-2_554delAGTT	p.Leu185fs	frameshift splice_acceptor splice_region intron	Exon 7 of 13	ENSP00000381538.2	Q8N5Y2-3

Frequencies

GnomAD3 genomes Cov.: 24

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 24

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Basilicata-Akhtar syndrome (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.6

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		3.0
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.86		Position offset: 7
DS_AL_spliceai		1.0		Position offset: 3

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

Other links and lift over

dbSNP: rs2147244798; hg19: chrX-11780953;