X-11758727-C-T

Variant names:

• chrX-11758727-C-T
• rs1601764289
• NM_078629.4:c.102+362C>T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001193270.2(MSL3):​c.20C>T​(p.Pro7Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000019 in 1,053,236 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 10/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000019 (0 hom. 2 hem.)
• Consequence: MSL3 NM_001193270.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.725

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08201876).
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSL3	NM_078629.4	c.102+362C>T		intron_variant	Intron 1 of 12	ENST00000312196.10	NP_523353.2
MSL3	NM_001193270.2	c.20C>T	p.Pro7Leu	missense_variant	Exon 1 of 13		NP_001180199.1
MSL3	NM_078628.2	c.102+362C>T		intron_variant	Intron 1 of 8		NP_523352.1
MSL3	NM_001282174.1	c.-263+362C>T		intron_variant	Intron 1 of 11		NP_001269103.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSL3	ENST00000312196.10	c.102+362C>T		intron_variant	Intron 1 of 12	1	NM_078629.4	ENSP00000312244.4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000190 AC: 2 AN: 1053236 Hom.: 0 Cov.: 31 AF XY: 0.00000580 AC XY: 2 AN XY: 344634

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: 0.0000451

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

MSL3-related disorder Uncertain:1

Mar 07, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MSL3 c.20C>T variant is predicted to result in the amino acid substitution p.Pro7Leu. 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
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.1
DANN	Uncertain	1.0
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.48	T;.
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.082	T;T
MetaSVM	Benign	-0.99	T
PROVEAN	Benign	-0.16	N;.
REVEL	Benign	0.025
Sift	Pathogenic	0.0	D;.
Vest4		0.20
MutPred		0.26		Loss of disorder (P = 0.0016);Loss of disorder (P = 0.0016);
MVP		0.043
ClinPred		0.12	T
GERP RS		-1.5

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: rs1601764289; hg19: chrX-11776846;