Variant 12-51101963-T-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_005653.5(TFCP2):c.1123A>T(p.Ile375Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TFCP2
NM_005653.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.78

Variant links:

Genes affected

TFCP2 (HGNC:11748): (transcription factor CP2) This gene encodes a transcription factor that binds the alpha-globin promoter and activates transcription of the alpha-globin gene. The encoded protein regulates erythroid gene expression, plays a role in the transcriptional switch of globin gene promoters, and it activates many other cellular and viral gene promoters. The gene product interacts with certain inflammatory response factors, and polymorphisms of this gene may be involved in the pathogenesis of Alzheimer's disease. [provided by RefSeq, Mar 2010]

TFCP2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.82

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TFCP2	NM_005653.5 link	c.1123A>T	p.Ile375Phe	missense_variant	11/15	ENST00000257915.10	NP_005644.2	Q12800-1A0A024R120
TFCP2	NM_001173452.2 link	c.1123A>T	p.Ile375Phe	missense_variant	11/15		NP_001166923.1	Q12800-4
TFCP2	NM_001173453.2 link	c.970A>T	p.Ile324Phe	missense_variant	10/14		NP_001166924.1	Q12800-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TFCP2	ENST00000257915.10 link	c.1123A>T	p.Ile375Phe	missense_variant	11/15	1	NM_005653.5	ENSP00000257915.5		Q12800-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251042

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135746

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:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460872

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726822

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:

0.00000180

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

Jan 06, 2023

The c.1123A>T (p.I375F) alteration is located in exon 11 (coding exon 11) of the TFCP2 gene. This alteration results from a A to T substitution at nucleotide position 1123, causing the isoleucine (I) at amino acid position 375 to be replaced by a phenylalanine (F). 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

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.24

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.84

D;.;T

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.82

D;D;D

MetaSVM

Uncertain

-0.0076

MutationAssessor

Pathogenic

3.0

M;.;.

PrimateAI

Pathogenic

0.89

PROVEAN

Uncertain

-3.7

D;D;D

REVEL

Uncertain

0.60

Sift

Uncertain

0.0010

D;D;D

Sift4G

Uncertain

0.0090

D;D;D

Polyphen

0.98

D;D;.

Vest4

0.84

MutPred

0.45

Gain of catalytic residue at A372 (P = 0);.;.;

MVP

0.92

MPC

2.3

ClinPred

1.0

GERP RS

4.9

Varity_R

0.71

gMVP

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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