3-136151356-T-G

Variant names:

• chr3-136151356-T-G
• rs1559954217
• NM_018133.4:c.1525A>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_018133.4(MSL2):​c.1525A>C​(p.Lys509Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MSL2 NM_018133.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02
• Publications: 0 publications found

Genes affected

MSL2 (HGNC:25544): (MSL complex subunit 2) Predicted to enable ubiquitin protein ligase activity. Involved in histone H4-K16 acetylation. Part of MSL complex. [provided by Alliance of Genome Resources, Apr 2022]

MSL2 Gene-Disease associations (from GenCC):

• Karayol-Borroto-Haghshenas neurodevelopmental syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• complex neurodevelopmental disorder

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4192515).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018133.4. 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
	MSL2	NM_018133.4	MANE Select	c.1525A>C	p.Lys509Gln	missense	Exon 2 of 2	NP_060603.2
	MSL2	NM_001145417.2		c.1303A>C	p.Lys435Gln	missense	Exon 2 of 2	NP_001138889.1	Q9HCI7-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSL2	ENST00000309993.3	TSL:1 MANE Select	c.1525A>C	p.Lys509Gln	missense	Exon 2 of 2	ENSP00000311827.2	Q9HCI7-1
	MSL2	ENST00000703105.1		c.1513A>C	p.Lys505Gln	missense	Exon 2 of 2	ENSP00000515172.1	A0A8V8TR57
	MSL2	ENST00000434835.2	TSL:2	c.1303A>C	p.Lys435Gln	missense	Exon 2 of 2	ENSP00000387948.2	Q9HCI7-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251320 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461854 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727228

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111994

Other (OTH) AF: 0.00 AC: 0 AN: 60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.42	T
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	0.90	L
PhyloP100		8.0
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.57
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.062	T
Polyphen		1.0	D
Vest4		0.61
MutPred		0.33		Loss of ubiquitination at K509 (P = 0.0074)
MVP		0.25
MPC		1.4
ClinPred		0.87	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.27
gMVP		0.85
Mutation Taster		=50/50

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: rs1559954217; hg19: chr3-135870198;