Variant X-11761531-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_078629.4(MSL3):c.414C>G(p.Asn138Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000894 in 111,903 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 24)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

MSL3
NM_078629.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.994

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06472087).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSL3	NM_078629.4 linkuse as main transcript	c.414C>G	p.Asn138Lys	missense_variant	5/13	ENST00000312196.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSL3	ENST00000312196.10 linkuse as main transcript	c.414C>G	p.Asn138Lys	missense_variant	5/13	1	NM_078629.4	P4	Q8N5Y2-1

Frequencies

GnomAD3 genomes

AF:

0.00000894

AC:

AN:

111903

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34125

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1087277

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

353991

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000894

AC:

AN:

111903

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34125

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000188

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

MSL3-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 29, 2023

The MSL3 c.414C>G variant is predicted to result in the amino acid substitution p.Asn138Lys. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.93

Cadd

Benign

9.7

Dann

Benign

0.32

DEOGEN2

Benign

0.020

T;.;.;.;.

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.59

T;T;T;T;T

M_CAP

Benign

0.0074

MetaRNN

Benign

0.065

T;T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.0

N;N;.;.;.

MutationTaster

Benign

1.0

D;D;N;N;N

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.77

N;N;.;.;N

REVEL

Benign

0.016

Sift

Benign

0.30

T;T;.;.;T

Sift4G

Benign

0.85

T;T;.;.;T

Polyphen

0.0

B;.;.;.;.

Vest4

0.077

MutPred

0.34

Gain of ubiquitination at N138 (P = 0.0114);Gain of ubiquitination at N138 (P = 0.0114);Gain of ubiquitination at N138 (P = 0.0114);Gain of ubiquitination at N138 (P = 0.0114);.;

MVP

0.28

MPC

0.71

ClinPred

0.096

GERP RS

0.39

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.11

gMVP

0.092

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

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