X-11760913-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS2

The NM_078629.4(MSL3):c.358G>A(p.Glu120Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000269 in 1,079,091 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.000027 (0 hom. 7 hem.)
• Consequence: MSL3 NM_078629.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.73

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.081608206).
• BP6: Variant X-11760913-G-A is Benign according to our data. Variant chrX-11760913-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3037087.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAdExome at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSL3	NM_078629.4	c.358G>A	p.Glu120Lys	missense_variant	4/13	ENST00000312196.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSL3	ENST00000312196.10	c.358G>A	p.Glu120Lys	missense_variant	4/13	1	NM_078629.4	P4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD3 exomes AF: 0.000148 AC: 23 AN: 155134 Hom.: 0 AF XY: 0.000133 AC XY: 6 AN XY: 45086

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000904

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: 0.00

Gnomad OTH exome AF: 0.000254

GnomAD4 exome AF: 0.0000269 AC: 29 AN: 1079091 Hom.: 0 Cov.: 27 AF XY: 0.0000202 AC XY: 7 AN XY: 347299

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000833

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: 0.0000221

GnomAD4 genome Cov.: 24

Bravo AF: 0.0000302

ExAC AF: 0.0000580 AC: 7

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

MSL3-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 17, 2022

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	0.12
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.56
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.018	T;.;.;.;.
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D;D;D;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.082	T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.8	L;L;.;.;.
MutationTaster	Benign	0.55	D;D;D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.59	N;N;.;.;N
REVEL	Benign	0.083
Sift	Benign	0.24	T;T;.;.;D
Sift4G	Benign	0.18	T;T;.;.;T
Polyphen		0.60	P;.;.;.;.
Vest4		0.20
MutPred		0.37		Gain of ubiquitination at E120 (P = 0.0048);Gain of ubiquitination at E120 (P = 0.0048);Gain of ubiquitination at E120 (P = 0.0048);Gain of ubiquitination at E120 (P = 0.0048);.;
MVP		0.29
MPC		0.75
ClinPred		0.035	T
GERP RS		4.6
Varity_R		0.30
gMVP		0.41

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

Other links and lift over

dbSNP: rs762777627; hg19: chrX-11779032;