rs1555907626

Variant names:

• chrX-11772256-G-T
• rs1555907626
• NM_078629.4:c.1381+1G>T

Variant summary

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

The NM_078629.4(MSL3):​c.1381+1G>T variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: MSL3 NM_078629.4 splice_donor, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.78
• 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: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-11772256-G-T is Pathogenic according to our data. Variant chrX-11772256-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 487564.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.1381+1G>T		splice_donor_variant, intron_variant	Intron 11 of 12	ENST00000312196.10	NP_523353.2
MSL3	NM_001193270.2	c.1345+1G>T		splice_donor_variant, intron_variant	Intron 11 of 12		NP_001180199.1
MSL3	NM_001282174.1	c.934+1G>T		splice_donor_variant, intron_variant	Intron 10 of 11		NP_001269103.1
MSL3	NM_006800.4	c.883+1G>T		splice_donor_variant, intron_variant	Intron 10 of 11		NP_006791.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSL3	ENST00000312196.10	c.1381+1G>T		splice_donor_variant, intron_variant	Intron 11 of 12	1	NM_078629.4	ENSP00000312244.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Basilicata-Akhtar syndrome Pathogenic:1

Dec 12, 2019

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	31
DANN	Uncertain	0.99
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		8.8
GERP RS		4.9
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DL_spliceai		1.0		Position offset: -1

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

Other links and lift over

dbSNP: rs1555907626; hg19: chrX-11790375;