Genetic Variant NM_078629.4:c.383C>A (chrX-11761500-C-A) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2

The NM_078629.4(MSL3):c.383C>A(p.Ser128*) variant causes a stop gained, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S128S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 24)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

MSL3
NM_078629.4 stop_gained, splice_region

Scores

Splicing: ADA: 0.00005050

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.11

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

Basilicata-Akhtar syndrome
Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

MSL3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MSL3	NM_078629.4	MANE Select	c.383C>A	p.Ser128*	stop_gained splice_region	Exon 5 of 13	NP_523353.2	Q8N5Y2-1
MSL3	NM_001193270.2		c.347C>A	p.Ser116*	stop_gained splice_region	Exon 5 of 13	NP_001180199.1	Q8N5Y2-3
MSL3	NM_078628.2		c.383C>A	p.Ser128*	stop_gained splice_region	Exon 5 of 9	NP_523352.1	Q8N5Y2-5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MSL3	ENST00000312196.10	TSL:1 MANE Select	c.383C>A	p.Ser128*	stop_gained splice_region	Exon 5 of 13	ENSP00000312244.4	Q8N5Y2-1
MSL3	ENST00000647869.1		c.383C>A	p.Ser128*	stop_gained splice_region	Exon 5 of 13	ENSP00000497615.1	A0A3B3IT59
MSL3	ENST00000398527.7	TSL:2	c.347C>A	p.Ser116*	stop_gained splice_region	Exon 5 of 13	ENSP00000381538.2	Q8N5Y2-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

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

AF:

0.00

AC:

AN:

1073070

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

342618

African (AFR)

AF:

0.00

AC:

AN:

25509

American (AMR)

AF:

0.00

AC:

AN:

32830

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18926

East Asian (EAS)

AF:

0.00

AC:

AN:

29501

South Asian (SAS)

AF:

0.00

AC:

AN:

50656

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40226

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4054

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

826210

Other (OTH)

AF:

0.00

AC:

AN:

45158

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

FATHMM_MKL

Uncertain

0.87

PhyloP100

5.1

Vest4

0.72

GERP RS

3.5

Mutation Taster

=16/184

disease causing (fs/PTC)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000050

dbscSNV1_RF

Benign

0.0060

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over