Variant chrX-139597520-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001171876.2(MCF2):c.2223G>A(p.Met741Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000462 in 1,081,116 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.0000046 ( 0 hom. 1 hem. )

Consequence

MCF2
NM_001171876.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.56

Variant links:

Genes affected

MCF2 (HGNC:6940): (MCF.2 cell line derived transforming sequence) The oncogenic protein encoded by this gene is a guanine nucleotide exchange factor (GEF) that exerts control over some members of the Rho family of small GTPases. Several transcript variants encoding different isoforms have been found for this gene. These isoforms exhibit different expression patterns and varying levels of GEF activity.[provided by RefSeq, Jan 2010]

MCF2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.19370523).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCF2	NM_001171876.2 linkuse as main transcript	c.2223G>A	p.Met741Ile	missense_variant	22/29	ENST00000519895.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCF2	ENST00000519895.6 linkuse as main transcript	c.2223G>A	p.Met741Ile	missense_variant	22/29	2	NM_001171876.2	P4	P10911-5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000113

AC:

AN:

176528

Hom.:

AF XY:

0.0000324

AC XY:

AN XY:

61636

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000252

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000462

AC:

AN:

1081116

Hom.:

Cov.:

AF XY:

0.00000287

AC XY:

AN XY:

348798

show subpopulations

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000603

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 25, 2022

The c.2223G>A (p.M741I) alteration is located in exon 22 (coding exon 21) of the MCF2 gene. This alteration results from a G to A substitution at nucleotide position 2223, causing the methionine (M) at amino acid position 741 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.11

.;T;.;.;T;.;.;.

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.85

T;T;T;T;T;T;T;T

M_CAP

Uncertain

0.29

MetaRNN

Benign

0.19

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.74

MutationAssessor

Benign

1.3

.;L;.;.;.;.;L;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D

PrimateAI

Benign

0.48

PROVEAN

Benign

-1.0

.;N;N;N;N;N;N;N

REVEL

Benign

0.12

Sift

Benign

0.83

.;T;T;T;T;T;T;T

Sift4G

Benign

0.61

.;T;T;T;T;T;T;T

Polyphen

0.56, 0.51, 1.0

.;P;.;.;.;.;P;D

Vest4

0.32, 0.36, 0.28, 0.31, 0.27, 0.31

MVP

0.61

MPC

0.28

ClinPred

0.20

GERP RS

3.9

Varity_R

0.45

gMVP

0.79

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over