10-110207935-G-T

Variant names:

• chr10-110207935-G-T
• rs141964073
• NM_130439.3:c.127G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_130439.3(MXI1):​c.127G>T​(p.Ala43Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000128 in 1,559,498 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 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. A43T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: MXI1 NM_130439.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.53
• Publications: 5 publications found

Genes affected

MXI1 (HGNC:7534): (MAX interactor 1, dimerization protein) Expression of the c-myc gene, which produces an oncogenic transcription factor, is tightly regulated in normal cells but is frequently deregulated in human cancers. The protein encoded by this gene is a transcriptional repressor thought to negatively regulate MYC function, and is therefore a potential tumor suppressor. This protein inhibits the transcriptional activity of MYC by competing for MAX, another basic helix-loop-helix protein that binds to MYC and is required for its function. Defects in this gene are frequently found in patients with prostate tumors. Three alternatively spliced transcripts encoding different isoforms have been described. Additional alternatively spliced transcripts may exist but the products of these transcripts have not been verified experimentally. [provided by RefSeq, Jul 2008]

ENSG00000228417 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15600792).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MXI1	NM_130439.3	c.127G>T	p.Ala43Ser	missense_variant	Exon 1 of 6	ENST00000332674.9	NP_569157.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MXI1	ENST00000332674.9	c.127G>T	p.Ala43Ser	missense_variant	Exon 1 of 6	1	NM_130439.3	ENSP00000331152.5
MXI1	ENST00000453116.5	c.127G>T	p.Ala43Ser	missense_variant	Exon 1 of 4	5		ENSP00000398981.1
ENSG00000228417	ENST00000451656.1	n.385C>A		non_coding_transcript_exon_variant	Exon 3 of 3	3
ENSG00000303571	ENST00000795696.1	n.-111C>A		upstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.00000664 AC: 1 AN: 150560 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

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: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 7.10e-7 AC: 1 AN: 1408938 Hom.: 0 Cov.: 32 AF XY: 0.00000143 AC XY: 1 AN XY: 700598

⚠️ 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: 29730

American (AMR) AF: 0.00 AC: 0 AN: 39046

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24512

East Asian (EAS) AF: 0.00 AC: 0 AN: 33542

South Asian (SAS) AF: 0.00 AC: 0 AN: 82062

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51654

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4818

European-Non Finnish (NFE) AF: 9.21e-7 AC: 1 AN: 1085998

Other (OTH) AF: 0.00 AC: 0 AN: 57576

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000664 AC: 1 AN: 150560 Hom.: 0 Cov.: 31 AF XY: 0.0000136 AC XY: 1 AN XY: 73500

African (AFR) AF: 0.00 AC: 0 AN: 41252

American (AMR) AF: 0.00 AC: 0 AN: 15130

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3450

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9912

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67520

Other (OTH) AF: 0.00 AC: 0 AN: 2076

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	18
DANN	Uncertain	0.99
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.75	T;T
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-1.0	T
PhyloP100		4.5
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.19	N;N
REVEL	Benign	0.10
Sift	Benign	0.34	T;D
Sift4G	Benign	0.077	T;T
Polyphen		0.0	B;.
Vest4		0.11
MutPred		0.16		Gain of glycosylation at A43 (P = 0.0014);Gain of glycosylation at A43 (P = 0.0014);
MVP		0.21
MPC		0.53
ClinPred		0.81	D
GERP RS		2.5
PromoterAI		-0.016	Neutral
gMVP		0.33
Mutation Taster		=95/5	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: rs141964073; hg19: chr10-111967693;