10-110207935-G-A

Position:

• chr10-110207935-G-A

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.127G>A​(p.Ala43Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00264 in 1,559,600 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0027 (9 hom.)
• Consequence: MXI1 NM_130439.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.53

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=0.008568615).
• BP6: Variant 10-110207935-G-A is Benign according to our data. Variant chr10-110207935-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3052445.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr10-110207935-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00194 (293/150670) while in subpopulation NFE AF= 0.00332 (224/67510). AF 95% confidence interval is 0.00296. There are 0 homozygotes in gnomad4. There are 122 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 9 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MXI1	NM_130439.3	c.127G>A	p.Ala43Thr	missense_variant	1/6	ENST00000332674.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MXI1	ENST00000332674.9	c.127G>A	p.Ala43Thr	missense_variant	1/6	1	NM_130439.3
	ENST00000451656.1	n.385C>T		non_coding_transcript_exon_variant	3/3	3
MXI1	ENST00000453116.5	c.127G>A	p.Ala43Thr	missense_variant	1/4	5

Frequencies

GnomAD3 genomes AF: 0.00195 AC: 293 AN: 150560 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000703

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00165

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.000202

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00332

Gnomad OTH AF: 0.00241

GnomAD3 exomes AF: 0.00163 AC: 343 AN: 210358 Hom.: 1 AF XY: 0.00181 AC XY: 210 AN XY: 116200

Gnomad AFR exome AF: 0.000355

Gnomad AMR exome AF: 0.000865

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00132

Gnomad FIN exome AF: 0.000286

Gnomad NFE exome AF: 0.00279

Gnomad OTH exome AF: 0.00124

GnomAD4 exome AF: 0.00272 AC: 3832 AN: 1408930 Hom.: 9 Cov.: 32 AF XY: 0.00265 AC XY: 1854 AN XY: 700596

Gnomad4 AFR exome AF: 0.000605

Gnomad4 AMR exome AF: 0.000973

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00124

Gnomad4 FIN exome AF: 0.000484

Gnomad4 NFE exome AF: 0.00323

Gnomad4 OTH exome AF: 0.00247

GnomAD4 genome AF: 0.00194 AC: 293 AN: 150670 Hom.: 0 Cov.: 31 AF XY: 0.00166 AC XY: 122 AN XY: 73618

Gnomad4 AFR AF: 0.000701

Gnomad4 AMR AF: 0.00165

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.000202

Gnomad4 NFE AF: 0.00332

Gnomad4 OTH AF: 0.00238

Alfa AF: 0.00204 Hom.: 0

Bravo AF: 0.00184

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00349 AC: 30

ExAC AF: 0.00164 AC: 199

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

MXI1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 21, 2020

This variant is classified as likely 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	-0.56	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	19
DANN	Uncertain	0.99
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.70	T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.0086	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.99	N
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.29	N;N
REVEL	Benign	0.088
Sift	Uncertain	0.0070	D;D
Sift4G	Benign	0.23	T;D
Polyphen		0.025	B;.
Vest4		0.20
MVP		0.18
MPC		0.55
ClinPred		0.061	T
GERP RS		2.5
gMVP		0.39

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: rs141964073; hg19: chr10-111967693; COSMIC: COSV100221822; COSMIC: COSV100221822;