X-11760863-G-T

Variant names:

• chrX-11760863-G-T
• rs768171462
• NM_078629.4:c.308G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_078629.4(MSL3):​c.308G>T​(p.Arg103Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000921 in 1,085,229 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R103H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: MSL3 NM_078629.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.89
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• Basilicata-Akhtar syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_078629.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSL3	NM_078629.4	MANE Select	c.308G>T	p.Arg103Leu	missense	Exon 4 of 13	NP_523353.2	Q8N5Y2-1
	MSL3	NM_001193270.2		c.272G>T	p.Arg91Leu	missense	Exon 4 of 13	NP_001180199.1	Q8N5Y2-3
	MSL3	NM_078628.2		c.308G>T	p.Arg103Leu	missense	Exon 4 of 9	NP_523352.1	Q8N5Y2-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSL3	ENST00000312196.10	TSL:1 MANE Select	c.308G>T	p.Arg103Leu	missense	Exon 4 of 13	ENSP00000312244.4	Q8N5Y2-1
	MSL3	ENST00000647869.1		c.308G>T	p.Arg103Leu	missense	Exon 4 of 13	ENSP00000497615.1	A0A3B3IT59
	MSL3	ENST00000398527.7	TSL:2	c.272G>T	p.Arg91Leu	missense	Exon 4 of 13	ENSP00000381538.2	Q8N5Y2-3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.21e-7 AC: 1 AN: 1085229 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 352877

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000384 AC: 1 AN: 26016

American (AMR) AF: 0.00 AC: 0 AN: 33755

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19040

East Asian (EAS) AF: 0.00 AC: 0 AN: 29812

South Asian (SAS) AF: 0.00 AC: 0 AN: 51430

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40068

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4116

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 835434

Other (OTH) AF: 0.00 AC: 0 AN: 45558

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.57	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		5.9
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.25
Sift	Benign	0.18	T
Sift4G	Uncertain	0.012	D
Polyphen		0.99	D
Vest4		0.38
MutPred		0.47		Loss of solvent accessibility (P = 0.0022)
MVP		0.44
MPC		0.83
ClinPred		0.97	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.58
gMVP		0.61
Mutation Taster		=199/101	polymorphism

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

Other links and lift over

dbSNP: rs768171462; hg19: chrX-11778982;