X-11762184-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_078629.4(MSL3):c.520A>G(p.Ile174Val) variant causes a missense change. The variant allele was found at a frequency of 0.000116 in 1,162,473 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 49 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.00013 ( 0 hom. 49 hem. )

Consequence

MSL3
NM_078629.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 6.02

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.05978009).

BP6

Variant X-11762184-A-G is Benign according to our data. Variant chrX-11762184-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2409871.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-11762184-A-G is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAdExome at 8 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSL3	NM_078629.4 linkuse as main transcript	c.520A>G	p.Ile174Val	missense_variant	6/13	ENST00000312196.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSL3	ENST00000312196.10 linkuse as main transcript	c.520A>G	p.Ile174Val	missense_variant	6/13	1	NM_078629.4	P4	Q8N5Y2-1

Frequencies

GnomAD3 genomes

AF:

0.0000178

AC:

AN:

112580

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34722

show subpopulations

Gnomad AFR

AF:

0.0000323

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000187

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000144

AC:

AN:

153153

Hom.:

AF XY:

0.000163

AC XY:

AN XY:

49219

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000109

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000914

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000960

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000127

AC:

133

AN:

1049893

Hom.:

Cov.:

AF XY:

0.000149

AC XY:

AN XY:

329811

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000111

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000694

Gnomad4 SAS exome

AF:

0.000705

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000945

Gnomad4 OTH exome

AF:

0.000271

GnomAD4 genome

AF:

0.0000178

AC:

AN:

112580

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34722

show subpopulations

Gnomad4 AFR

AF:

0.0000323

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000187

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000567

ExAC

AF:

0.000239

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 17, 2022

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2023

MSL3: BP4, BS2 -

MSL3-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 17, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.26

Cadd

Benign

Dann

Uncertain

1.0

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.78

T;T;T;T;T;T;.;.;.;.;.;.;T;T;.;T;T;T;T;.;.;T;T

M_CAP

Benign

0.050

MetaRNN

Benign

0.060

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.68

MutationTaster

Benign

0.80

D;D;D;D;N

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.65

N;N;N;.;.;N;N;.;.;.;.;.;N;N;.;.;.;.;.;.;.;.;.

REVEL

Benign

0.12

Sift

Benign

0.24

T;D;D;.;.;D;.;.;.;.;.;.;T;T;.;.;.;.;.;.;.;.;.

Sift4G

Benign

0.40

T;T;T;.;.;T;.;.;.;.;.;.;T;T;.;.;.;.;.;.;.;.;.

Polyphen

0.098

.;B;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

Vest4

0.18

MVP

0.77

MPC

0.56

ClinPred

0.11

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.18

gMVP

0.23

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over