2-42644172-C-G

Variant names:

• chr2-42644172-C-G
• rs368239450
• NM_001330442.2:c.427C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP2 PP3

The NM_001330442.2(MTA3):​c.427C>G​(p.Leu143Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000868 in 1,612,938 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: MTA3 NM_001330442.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.66
• Publications: 0 publications found

Genes affected

MTA3 (HGNC:23784): (metastasis associated 1 family member 3) Predicted to enable histone deacetylase binding activity; transcription coactivator activity; and transcription corepressor activity. Involved in negative regulation of transcription, DNA-templated. Located in nucleoplasm. Part of NuRD complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.65794 (below the threshold of 3.09). Trascript score misZ: -0.24302 (below the threshold of 3.09).
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.785

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001330442.2. 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
	MTA3	NM_001330442.2	MANE Select	c.427C>G	p.Leu143Val	missense	Exon 6 of 17	NP_001317371.1	Q9BTC8-1
	MTA3	NM_001330443.2		c.427C>G	p.Leu143Val	missense	Exon 6 of 17	NP_001317372.1
	MTA3	NM_001282755.2		c.259C>G	p.Leu87Val	missense	Exon 7 of 18	NP_001269684.1	F6RRE2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTA3	ENST00000405094.2	TSL:5 MANE Select	c.427C>G	p.Leu143Val	missense	Exon 6 of 17	ENSP00000385823.1	Q9BTC8-1
	MTA3	ENST00000406652.5	TSL:1	c.259C>G	p.Leu87Val	missense	Exon 6 of 17	ENSP00000384249.1	F6RRE2
	MTA3	ENST00000407270.7	TSL:1	c.427C>G	p.Leu143Val	missense	Exon 6 of 14	ENSP00000385045.3	Q9BTC8-2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

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

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1460794 Hom.: 0 Cov.: 29 AF XY: 0.00000688 AC XY: 5 AN XY: 726672

⚠️ 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: 33424

American (AMR) AF: 0.00 AC: 0 AN: 44602

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39586

South Asian (SAS) AF: 0.00 AC: 0 AN: 86118

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000900 AC: 10 AN: 1111494

Other (OTH) AF: 0.0000166 AC: 1 AN: 60322

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00218213), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152144 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74326

African (AFR) AF: 0.0000483 AC: 2 AN: 41424

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

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	0.73
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D
Eigen	Benign	0.042
Eigen_PC	Benign	-0.082
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		2.7
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.62
Sift	Uncertain	0.026	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.99	D
Vest4		0.83
MutPred		0.45		Loss of stability (P = 0.0722)
MVP		0.89
MPC		0.67
ClinPred		0.94	D
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.54
Mutation Taster		=46/54	disease causing

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: rs368239450; hg19: chr2-42871312;