Genetic Variant MSL3:p.Leu308Pro (chrX-11765481-T-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2PP5_ModerateBP4

The NM_078629.4(MSL3):c.923T>C(p.Leu308Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 23)

Consequence

MSL3
NM_078629.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 5.02

Publications

0 publications found

Variant links:

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

MSL3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant X-11765481-T-C is Pathogenic according to our data. Variant chrX-11765481-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 487567.Status of the report is criteria_provided_single_submitter, 1 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.25802967). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_078629.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MSL3	NM_078629.4	MANE Select	c.923T>C	p.Leu308Pro	missense	Exon 9 of 13	NP_523353.2
MSL3	NM_001193270.2		c.887T>C	p.Leu296Pro	missense	Exon 9 of 13	NP_001180199.1
MSL3	NM_078628.2		c.923T>C	p.Leu308Pro	missense	Exon 9 of 9	NP_523352.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MSL3	ENST00000312196.10	TSL:1 MANE Select	c.923T>C	p.Leu308Pro	missense	Exon 9 of 13	ENSP00000312244.4
MSL3	ENST00000647869.1		c.920T>C	p.Leu307Pro	missense	Exon 9 of 13	ENSP00000497615.1
MSL3	ENST00000398527.7	TSL:2	c.887T>C	p.Leu296Pro	missense	Exon 9 of 13	ENSP00000381538.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Basilicata-Akhtar syndrome

Pathogenic:1

Aug 05, 2022

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.040

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.76

M_CAP

Benign

0.021

MetaRNN

Benign

0.26

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

PhyloP100

5.0

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-2.0

REVEL

Benign

0.16

Sift

Benign

0.17

Sift4G

Benign

0.16

Polyphen

0.0060

Vest4

0.47

MutPred

0.46

Gain of relative solvent accessibility (P = 0.005)

MVP

0.42

MPC

1.1

ClinPred

0.59

GERP RS

4.7

PromoterAI

0.0073

Neutral

(source)

Varity_R

0.80

gMVP

0.62

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over