chrX-11758324-G-A

Variant names:

• chrX-11758324-G-A
• NM_078629.4:c.61G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_078629.4(MSL3):​c.61G>A​(p.Glu21Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: MSL3 NM_078629.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.49

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-DT (HGNC:56856): (MSL3 divergent transcript)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSL3	NM_078629.4	c.61G>A	p.Glu21Lys	missense_variant	Exon 1 of 13	ENST00000312196.10	NP_523353.2
MSL3	NM_078628.2	c.61G>A	p.Glu21Lys	missense_variant	Exon 1 of 9		NP_523352.1
MSL3	NM_001282174.1	c.-304G>A		5_prime_UTR_variant	Exon 1 of 12		NP_001269103.1
MSL3-DT	XR_007068393.1	n.-241C>T		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSL3	ENST00000312196.10	c.61G>A	p.Glu21Lys	missense_variant	Exon 1 of 13	1	NM_078629.4	ENSP00000312244.4

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1025787 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 326539

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 Cov.: 21

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

MSL3-related disorder Uncertain:1

Jul 16, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MSL3 c.61G>A variant is predicted to result in the amino acid substitution p.Glu21Lys. 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	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.27	T;.;.;.
FATHMM_MKL	Benign	0.65	D
LIST_S2	Uncertain	0.92	D;D;D;D
M_CAP	Pathogenic	0.78	D
MetaRNN	Uncertain	0.63	D;D;D;D
MetaSVM	Benign	-0.46	T
MutationAssessor	Uncertain	2.3	M;M;.;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-2.4	N;D;.;.
REVEL	Uncertain	0.38
Sift	Uncertain	0.0060	D;D;.;.
Sift4G	Uncertain	0.012	D;D;.;.
Polyphen		1.0	D;.;.;.
Vest4		0.58
MutPred		0.64		Gain of methylation at E21 (P = 0.0011);Gain of methylation at E21 (P = 0.0011);Gain of methylation at E21 (P = 0.0011);Gain of methylation at E21 (P = 0.0011);
MVP		0.42
MPC		1.7
ClinPred		0.98	D
GERP RS		3.0
Varity_R		0.68
gMVP		0.97

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-11776443;