2-42644131-C-G

Variant names:

• chr2-42644131-C-G
• rs761809163
• NM_001330442.2:c.386C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001330442.2(MTA3):​c.386C>G​(p.Thr129Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000697 in 1,433,940 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T129N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: MTA3 NM_001330442.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.21
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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).
• BP4: Computational evidence support a benign effect (MetaRNN=0.25679016).

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.386C>G	p.Thr129Ser	missense	Exon 6 of 17	NP_001317371.1	Q9BTC8-1
	MTA3	NM_001330443.2		c.386C>G	p.Thr129Ser	missense	Exon 6 of 17	NP_001317372.1
	MTA3	NM_001282755.2		c.218C>G	p.Thr73Ser	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.386C>G	p.Thr129Ser	missense	Exon 6 of 17	ENSP00000385823.1	Q9BTC8-1
	MTA3	ENST00000406652.5	TSL:1	c.218C>G	p.Thr73Ser	missense	Exon 6 of 17	ENSP00000384249.1	F6RRE2
	MTA3	ENST00000407270.7	TSL:1	c.386C>G	p.Thr129Ser	missense	Exon 6 of 14	ENSP00000385045.3	Q9BTC8-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.97e-7 AC: 1 AN: 1433940 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 713936

⚠️ 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: 32064

American (AMR) AF: 0.00 AC: 0 AN: 40604

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25316

East Asian (EAS) AF: 0.00 AC: 0 AN: 38592

South Asian (SAS) AF: 0.00 AC: 0 AN: 82024

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53070

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5642

European-Non Finnish (NFE) AF: 9.11e-7 AC: 1 AN: 1097396

Other (OTH) AF: 0.00 AC: 0 AN: 59232

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.038	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	22
DANN	Benign	0.93
DEOGEN2	Benign	0.32	T
Eigen	Benign	0.047
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.26	T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	0.63	N
PhyloP100		3.2
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.28
Sift	Benign	0.45	T
Sift4G	Benign	0.38	T
Polyphen		0.051	B
Vest4		0.33
MutPred		0.47		Gain of disorder (P = 0.0584)
MVP		0.43
MPC		0.17
ClinPred		0.57	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.082
gMVP		0.41
Mutation Taster		=58/42	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs761809163; hg19: chr2-42871271;