Variant X-11760495-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_078629.4(MSL3):c.278G>A(p.Arg93His) variant causes a missense change. The variant allele was found at a frequency of 0.0000047 in 1,063,804 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 24)

Exomes 𝑓: 0.0000047 ( 0 hom. 1 hem. )

Consequence

MSL3
NM_078629.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.60

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 Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.38299447).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSL3	NM_078629.4 linkuse as main transcript	c.278G>A	p.Arg93His	missense_variant	3/13	ENST00000312196.10	NP_523353.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSL3	ENST00000312196.10 linkuse as main transcript	c.278G>A	p.Arg93His	missense_variant	3/13	1	NM_078629.4	ENSP00000312244	P4	Q8N5Y2-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000592

AC:

AN:

168985

Hom.:

AF XY:

0.00

AC XY:

AN XY:

56155

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000129

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000470

AC:

AN:

1063804

Hom.:

Cov.:

AF XY:

0.00000299

AC XY:

AN XY:

334358

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000366

Gnomad4 OTH exome

AF:

0.0000447

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000227

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 18, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with MSL3-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 93 of the MSL3 protein (p.Arg93His). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.026

T;.;.;.;.

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.73

T;T;T;T;T

M_CAP

Pathogenic

0.48

MetaRNN

Benign

0.38

T;T;T;T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

1.7

L;L;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.47

N;N;.;.;N

REVEL

Benign

0.26

Sift

Benign

0.12

T;T;.;.;D

Sift4G

Benign

0.29

T;T;.;.;T

Polyphen

1.0

D;.;.;.;.

Vest4

0.34

MutPred

0.51

Loss of methylation at R93 (P = 0.012);Loss of methylation at R93 (P = 0.012);Loss of methylation at R93 (P = 0.012);Loss of methylation at R93 (P = 0.012);.;

MVP

0.69

MPC

1.8

ClinPred

0.82

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.38

gMVP

0.56

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