X-139585133-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001171876.2(MCF2):​c.2906C>T​(p.Ala969Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000345 in 1,202,039 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 138 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., 8 hem., cov: 22)
Exomes 𝑓: 0.00036 ( 0 hom. 130 hem. )

Consequence

MCF2
NM_001171876.2 missense

Scores

17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.460
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.046048254).
BS2
High Hemizygotes in GnomAd4 at 8 gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MCF2NM_001171876.2 linkuse as main transcriptc.2906C>T p.Ala969Val missense_variant 28/29 ENST00000519895.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MCF2ENST00000519895.6 linkuse as main transcriptc.2906C>T p.Ala969Val missense_variant 28/292 NM_001171876.2 P4P10911-5

Frequencies

GnomAD3 genomes
AF:
0.000189
AC:
21
AN:
111269
Hom.:
0
Cov.:
22
AF XY:
0.000239
AC XY:
8
AN XY:
33489
show subpopulations
Gnomad AFR
AF:
0.0000980
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000958
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:
0.000320
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000141
AC:
25
AN:
177020
Hom.:
0
AF XY:
0.000161
AC XY:
10
AN XY:
62086
show subpopulations
Gnomad AFR exome
AF:
0.000156
Gnomad AMR exome
AF:
0.0000383
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:
0.000263
Gnomad OTH exome
AF:
0.000232
GnomAD4 exome
AF:
0.000361
AC:
394
AN:
1090770
Hom.:
0
Cov.:
27
AF XY:
0.000364
AC XY:
130
AN XY:
356950
show subpopulations
Gnomad4 AFR exome
AF:
0.000153
Gnomad4 AMR exome
AF:
0.0000288
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000100
Gnomad4 SAS exome
AF:
0.0000380
Gnomad4 FIN exome
AF:
0.0000496
Gnomad4 NFE exome
AF:
0.000435
Gnomad4 OTH exome
AF:
0.000393
GnomAD4 genome
AF:
0.000189
AC:
21
AN:
111269
Hom.:
0
Cov.:
22
AF XY:
0.000239
AC XY:
8
AN XY:
33489
show subpopulations
Gnomad4 AFR
AF:
0.0000980
Gnomad4 AMR
AF:
0.0000958
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000320
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000436
Hom.:
3
Bravo
AF:
0.000174
TwinsUK
AF:
0.000809
AC:
3
ALSPAC
AF:
0.000346
AC:
1
ExAC
AF:
0.0000989
AC:
12

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 submitterclinical testingAmbry GeneticsMay 17, 2023The c.2906C>T (p.A969V) alteration is located in exon 28 (coding exon 27) of the MCF2 gene. This alteration results from a C to T substitution at nucleotide position 2906, causing the alanine (A) at amino acid position 969 to be replaced by a valine (V). 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
Benign
0.075
BayesDel_addAF
Benign
-0.64
T
BayesDel_noAF
Benign
-0.83
CADD
Benign
4.1
DANN
Benign
0.89
DEOGEN2
Benign
0.088
.;T;.;T;.;.
FATHMM_MKL
Benign
0.027
N
LIST_S2
Benign
0.19
T;T;T;T;T;T
M_CAP
Benign
0.0060
T
MetaRNN
Benign
0.046
T;T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
-0.34
.;N;.;.;.;.
MutationTaster
Benign
1.0
N;N;N;N;N;N;N;N
PrimateAI
Benign
0.24
T
PROVEAN
Benign
-1.0
.;N;N;N;N;N
REVEL
Benign
0.035
Sift
Benign
0.24
.;T;T;T;T;T
Sift4G
Benign
0.28
.;T;T;T;T;T
Polyphen
0.0010
.;B;.;.;.;B
Vest4
0.037, 0.030, 0.039, 0.035
MVP
0.34
MPC
0.25
ClinPred
0.0064
T
GERP RS
-2.1
Varity_R
0.042
gMVP
0.11

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.

Other links and lift over

dbSNP: rs777519579; hg19: chrX-138667292; API