X-11758268-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_078629.4(MSL3):c.5G>A(p.Ser2Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000105 in 952,862 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S2T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.0000010 (0 hom. 0 hem.)
• Consequence: MSL3 NM_078629.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.95

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17100435).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSL3	NM_078629.4	c.5G>A	p.Ser2Asn	missense_variant	1/13	ENST00000312196.10
MSL3	NM_078628.2	c.5G>A	p.Ser2Asn	missense_variant	1/9
MSL3	NM_001282174.1	c.-360G>A		5_prime_UTR_variant	1/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSL3	ENST00000312196.10	c.5G>A	p.Ser2Asn	missense_variant	1/13	1	NM_078629.4	P4

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome AF: 0.00000105 AC: 1 AN: 952862 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 292584

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: 0.00000132

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 21

Bravo AF: 0.0000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 07, 2022

The c.5G>A (p.S2N) alteration is located in exon 1 (coding exon 1) of the MSL3 gene. This alteration results from a G to A substitution at nucleotide position 5, causing the serine (S) at amino acid position 2 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.98
Cadd	Benign	22
Dann	Benign	0.94
DEOGEN2	Benign	0.018	T;.;.;.
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.73	T;T;T;T
M_CAP	Uncertain	0.099	D
MetaRNN	Benign	0.17	T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.69	N;N;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.020	N;N;.;.
REVEL	Benign	0.062
Sift	Benign	0.10	T;T;.;.
Sift4G	Benign	0.22	T;T;.;.
Polyphen		0.0	B;.;.;.
Vest4		0.077
MutPred		0.30		Loss of phosphorylation at S2 (P = 0.0118);Loss of phosphorylation at S2 (P = 0.0118);Loss of phosphorylation at S2 (P = 0.0118);Loss of phosphorylation at S2 (P = 0.0118);
MVP		0.27
MPC		0.58
ClinPred		0.16	T
GERP RS		1.3
Varity_R		0.21
gMVP		0.47

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: rs150938844; hg19: chrX-11776387;