10-110228228-C-T

Position:

• chr10-110228228-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP5_Moderate BP4

The NM_130439.3(MXI1):​c.314C>T​(p.Pro105Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,830 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 Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: MXI1 NM_130439.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.82

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-110228228-C-T is Pathogenic according to our data. Variant chr10-110228228-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2445390.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.20873424). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MXI1	NM_130439.3	c.314C>T	p.Pro105Leu	missense_variant	2/6	ENST00000332674.9
MXI1	NM_005962.5	c.113C>T	p.Pro38Leu	missense_variant	2/6
MXI1	NM_001008541.1	c.5C>T	p.Pro2Leu	missense_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MXI1	ENST00000332674.9	c.314C>T	p.Pro105Leu	missense_variant	2/6	1	NM_130439.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461830 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727214

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Ovarian cancer Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University

Jan 01, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	.;.;.;T;T;.;.
Eigen	Benign	0.035
Eigen_PC	Benign	0.069
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.21	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	.;.;.;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.9	N;N;N;N;N;N;N
REVEL	Benign	0.068
Sift	Uncertain	0.0070	D;D;D;D;D;D;D
Sift4G	Uncertain	0.047	D;D;D;D;D;D;D
Polyphen		0.99	D;.;.;P;P;.;P
Vest4		0.68
MutPred		0.21		.;.;.;Loss of glycosylation at P38 (P = 0.0306);Loss of glycosylation at P38 (P = 0.0306);.;.;
MVP		0.20
MPC		1.0
ClinPred		0.91	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.075
gMVP		0.36

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

Publications

LitVar

Other links and lift over

dbSNP: rs1564709391; hg19: chr10-111987986; COSMIC: COSV99491605;