3-183179578-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_015078.4(MCF2L2):ā€‹c.3220A>Gā€‹(p.Thr1074Ala) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000235 in 1,614,012 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/25 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000013 ( 0 hom., cov: 32)
Exomes š‘“: 0.000025 ( 0 hom. )

Consequence

MCF2L2
NM_015078.4 missense, splice_region

Scores

19
Splicing: ADA: 0.9730
1
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.380
Variant links:
Genes affected
MCF2L2 (HGNC:30319): (MCF.2 cell line derived transforming sequence-like 2) Predicted to enable guanyl-nucleotide exchange factor activity. Predicted to be involved in regulation of catalytic activity. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MCF2L2NM_015078.4 linkuse as main transcriptc.3220A>G p.Thr1074Ala missense_variant, splice_region_variant 29/30 ENST00000328913.8
MCF2L2XM_011512585.3 linkuse as main transcriptc.2161A>G p.Thr721Ala missense_variant, splice_region_variant 21/22
MCF2L2XM_047447751.1 linkuse as main transcriptc.2119A>G p.Thr707Ala missense_variant, splice_region_variant 20/21

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MCF2L2ENST00000328913.8 linkuse as main transcriptc.3220A>G p.Thr1074Ala missense_variant, splice_region_variant 29/305 NM_015078.4 A2Q86YR7-1
MCF2L2ENST00000473233.5 linkuse as main transcriptc.3220A>G p.Thr1074Ala missense_variant 29/295 P4Q86YR7-4
MCF2L2ENST00000464626.1 linkuse as main transcriptn.356A>G non_coding_transcript_exon_variant 2/24
MCF2L2ENST00000478652.1 linkuse as main transcriptn.358A>G splice_region_variant, non_coding_transcript_exon_variant 2/33

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152226
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000797
AC:
2
AN:
251028
Hom.:
0
AF XY:
0.00000737
AC XY:
1
AN XY:
135736
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:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000246
AC:
36
AN:
1461786
Hom.:
0
Cov.:
31
AF XY:
0.0000303
AC XY:
22
AN XY:
727200
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:
0.0000306
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152226
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74370
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000386
Hom.:
0
Bravo
AF:
0.0000151
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

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 27, 2022The c.3220A>G (p.T1074A) alteration is located in exon 29 (coding exon 29) of the MCF2L2 gene. This alteration results from a A to G substitution at nucleotide position 3220, causing the threonine (T) at amino acid position 1074 to be replaced by an alanine (A). 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
0.064
BayesDel_addAF
Benign
-0.30
T
BayesDel_noAF
Benign
-0.60
CADD
Benign
13
DANN
Benign
0.95
DEOGEN2
Benign
0.00072
T;.
Eigen
Benign
-1.0
Eigen_PC
Benign
-1.0
FATHMM_MKL
Benign
0.042
N
LIST_S2
Benign
0.27
T;T
M_CAP
Benign
0.0025
T
MetaRNN
Benign
0.032
T;T
MetaSVM
Benign
-0.93
T
MutationAssessor
Benign
0.0
N;N
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.26
T
PROVEAN
Benign
-0.030
N;N
REVEL
Benign
0.020
Sift
Benign
0.41
T;D
Sift4G
Benign
0.75
T;D
Polyphen
0.0
B;.
Vest4
0.11
MutPred
0.23
Loss of phosphorylation at T1074 (P = 0.006);Loss of phosphorylation at T1074 (P = 0.006);
MVP
0.040
MPC
0.18
ClinPred
0.047
T
GERP RS
0.50
Varity_R
0.046
gMVP
0.078

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
0.97
dbscSNV1_RF
Benign
0.62
SpliceAI score (max)
0.34
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.34
Position offset: -1

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: rs756640415; hg19: chr3-182897366; API