X-11760495-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.60

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 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	UniProt
MSL3	NM_078629.4	c.278G>A	p.Arg93His	missense_variant	3/13	ENST00000312196.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSL3	ENST00000312196.10	c.278G>A	p.Arg93His	missense_variant	3/13	1	NM_078629.4	P4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD3 exomes AF: 0.00000592 AC: 1 AN: 168985 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 56155

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: 5 AN: 1063804 Hom.: 0 Cov.: 24 AF XY: 0.00000299 AC XY: 1 AN XY: 334358

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.: 24

Bravo AF: 0.0000227

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

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	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	22
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.026	T;.;.;.;.
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.73	T;T;T;T;T
M_CAP	Pathogenic	0.48	D
MetaRNN	Benign	0.38	T;T;T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.7	L;L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.55	T
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	D
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

Other links and lift over

dbSNP: rs753517099; hg19: chrX-11778614;