Genetic Variant NM_078629.4:c.16G>A (chrX-11758279-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_078629.4(MSL3):c.16G>A(p.Gly6Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.18

Variant links:

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 links:

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

MSL3-DT links:

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ACMG classification

Classification made for transcript

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=0.317811).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSL3	NM_078629.4 link	c.16G>A	p.Gly6Ser	missense_variant	Exon 1 of 13	ENST00000312196.10	NP_523353.2	Q8N5Y2-1
MSL3	NM_078628.2 link	c.16G>A	p.Gly6Ser	missense_variant	Exon 1 of 9		NP_523352.1	Q8N5Y2-5
MSL3	NM_001282174.1 link	c.-349G>A		5_prime_UTR_variant	Exon 1 of 12		NP_001269103.1	Q8N5Y2-6
MSL3-DT	XR_007068393.1 link	n.-196C>T		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSL3	ENST00000312196.10 link	c.16G>A	p.Gly6Ser	missense_variant	Exon 1 of 13	1	NM_078629.4	ENSP00000312244.4		Q8N5Y2-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

997890

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

313528

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.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

May 31, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.16G>A (p.G6S) 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 16, causing the glycine (G) at amino acid position 6 to be replaced by a serine (S). 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

Uncertain

0.48

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.41

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.053

T;.;.;.

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.80

T;T;T;T

M_CAP

Pathogenic

0.39

MetaRNN

Benign

0.32

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

L;L;.;.

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-1.9

N;N;.;.

REVEL

Benign

0.19

Sift

Pathogenic

0.0

D;T;.;.

Sift4G

Benign

0.22

T;T;.;.

Polyphen

0.11

B;.;.;.

Vest4

0.36

MutPred

0.20

Gain of phosphorylation at G6 (P = 0.0206);Gain of phosphorylation at G6 (P = 0.0206);Gain of phosphorylation at G6 (P = 0.0206);Gain of phosphorylation at G6 (P = 0.0206);

MVP

0.40

MPC

1.6

ClinPred

0.98

GERP RS

2.3

Varity_R

0.80

gMVP

0.79

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over