10-110207891-C-G

Position:

• chr10-110207891-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_130439.3(MXI1):​c.83C>G​(p.Pro28Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00148 in 1,365,504 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P28S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0026 (12 hom., cov: 31)
  • Exomes 𝑓: 0.0013 (30 hom.)
• Consequence: MXI1 NM_130439.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.79

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0024390817).
• BP6: Variant 10-110207891-C-G is Benign according to our data. Variant chr10-110207891-C-G is described in ClinVar as [Benign]. Clinvar id is 3037741.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00259 (388/149722) while in subpopulation EAS AF= 0.0476 (244/5126). AF 95% confidence interval is 0.0427. There are 12 homozygotes in gnomad4. There are 214 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 12 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MXI1	NM_130439.3	c.83C>G	p.Pro28Arg	missense_variant	1/6	ENST00000332674.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MXI1	ENST00000332674.9	c.83C>G	p.Pro28Arg	missense_variant	1/6	1	NM_130439.3
	ENST00000451656.1	n.429G>C		non_coding_transcript_exon_variant	3/3	3
MXI1	ENST00000453116.5	c.83C>G	p.Pro28Arg	missense_variant	1/4	5

Frequencies

GnomAD3 genomes AF: 0.00259 AC: 388 AN: 149614 Hom.: 12 Cov.: 31

Gnomad AFR AF: 0.00107

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000532

Gnomad ASJ AF: 0.000291

Gnomad EAS AF: 0.0475

Gnomad SAS AF: 0.00829

Gnomad FIN AF: 0.00125

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000462

Gnomad OTH AF: 0.00388

GnomAD3 exomes AF: 0.00248 AC: 185 AN: 74482 Hom.: 4 AF XY: 0.00248 AC XY: 107 AN XY: 43168

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000567

Gnomad ASJ exome AF: 0.000896

Gnomad EAS exome AF: 0.0493

Gnomad SAS exome AF: 0.00469

Gnomad FIN exome AF: 0.00144

Gnomad NFE exome AF: 0.000436

Gnomad OTH exome AF: 0.00258

GnomAD4 exome AF: 0.00135 AC: 1636 AN: 1215782 Hom.: 30 Cov.: 29 AF XY: 0.00139 AC XY: 830 AN XY: 598238

Gnomad4 AFR exome AF: 0.0000860

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.000581

Gnomad4 EAS exome AF: 0.0346

Gnomad4 SAS exome AF: 0.00514

Gnomad4 FIN exome AF: 0.00170

Gnomad4 NFE exome AF: 0.000185

Gnomad4 OTH exome AF: 0.00505

GnomAD4 genome AF: 0.00259 AC: 388 AN: 149722 Hom.: 12 Cov.: 31 AF XY: 0.00293 AC XY: 214 AN XY: 73114

Gnomad4 AFR AF: 0.00107

Gnomad4 AMR AF: 0.000531

Gnomad4 ASJ AF: 0.000291

Gnomad4 EAS AF: 0.0476

Gnomad4 SAS AF: 0.00829

Gnomad4 FIN AF: 0.00125

Gnomad4 NFE AF: 0.000462

Gnomad4 OTH AF: 0.00384

Alfa AF: 0.00114 Hom.: 2

Bravo AF: 0.00210

ExAC AF: 0.00233 AC: 253

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

MXI1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 30, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	17
DANN	Uncertain	0.99
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.54	T;T
MetaRNN	Benign	0.0024	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.86	N
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.18	N;N
REVEL	Benign	0.094
Sift	Uncertain	0.0060	D;D
Sift4G	Benign	0.72	T;T
Polyphen		0.98	D;.
Vest4		0.14
MVP		0.15
MPC		0.60
ClinPred		0.059	T
GERP RS		1.6
gMVP		0.18

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: rs201906236; hg19: chr10-111967649; COSMIC: COSV60311465; COSMIC: COSV60311465;