X-11760483-A-C

Variant names:

• chrX-11760483-A-C
• rs760206428
• NM_078629.4:c.266A>C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_078629.4(MSL3):​c.266A>C​(p.Lys89Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000503 in 1,192,504 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000036 (0 hom., 1 hem., cov: 24)
  • Exomes 𝑓: 0.0000019 (0 hom. 0 hem.)
• Consequence: MSL3 NM_078629.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.83
• Publications: 0 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: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.31671613).

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.266A>C	p.Lys89Thr	missense	Exon 3 of 13	NP_523353.2	Q8N5Y2-1
	MSL3	NM_001193270.2		c.230A>C	p.Lys77Thr	missense	Exon 3 of 13	NP_001180199.1	Q8N5Y2-3
	MSL3	NM_078628.2		c.266A>C	p.Lys89Thr	missense	Exon 3 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.266A>C	p.Lys89Thr	missense	Exon 3 of 13	ENSP00000312244.4	Q8N5Y2-1
	MSL3	ENST00000647869.1		c.266A>C	p.Lys89Thr	missense	Exon 3 of 13	ENSP00000497615.1	A0A3B3IT59
	MSL3	ENST00000398527.7	TSL:2	c.230A>C	p.Lys77Thr	missense	Exon 3 of 13	ENSP00000381538.2	Q8N5Y2-3

Frequencies

GnomAD3 genomes AF: 0.0000356 AC: 4 AN: 112430 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.000129

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000578 AC: 1 AN: 173142 AF XY: 0.00

Gnomad AFR exome AF: 0.0000793

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000185 AC: 2 AN: 1080074 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 348194

African (AFR) AF: 0.0000769 AC: 2 AN: 26003

American (AMR) AF: 0.00 AC: 0 AN: 33888

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19141

East Asian (EAS) AF: 0.00 AC: 0 AN: 29750

South Asian (SAS) AF: 0.00 AC: 0 AN: 51291

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40199

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3359

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 831097

Other (OTH) AF: 0.00 AC: 0 AN: 45346

GnomAD4 genome AF: 0.0000356 AC: 4 AN: 112430 Hom.: 0 Cov.: 24 AF XY: 0.0000289 AC XY: 1 AN XY: 34578

African (AFR) AF: 0.000129 AC: 4 AN: 30935

American (AMR) AF: 0.00 AC: 0 AN: 10629

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2645

East Asian (EAS) AF: 0.00 AC: 0 AN: 3641

South Asian (SAS) AF: 0.00 AC: 0 AN: 2743

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6081

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53320

Other (OTH) AF: 0.00 AC: 0 AN: 1512

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.080	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.8	L
PhyloP100		7.8
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.29
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.23	T
Polyphen		1.0	D
Vest4		0.60
MVP		0.54
MPC		1.8
ClinPred		0.58	D
GERP RS		4.8
PromoterAI		0.012	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.88
gMVP		0.76
Mutation Taster		=232/68	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: rs760206428; hg19: chrX-11778602;