12-51103696-A-G

Variant names:

• chr12-51103696-A-G
• NM_005653.5:c.1034T>C

Variant summary

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

The NM_005653.5(TFCP2):​c.1034T>C​(p.Phe345Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TFCP2 NM_005653.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.71

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]

ACMG classification

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 rank	MANE	Protein	UniProt
TFCP2	NM_005653.5	c.1034T>C	p.Phe345Ser	missense_variant	Exon 10 of 15	ENST00000257915.10	NP_005644.2
TFCP2	NM_001173452.2	c.1034T>C	p.Phe345Ser	missense_variant	Exon 10 of 15		NP_001166923.1
TFCP2	NM_001173453.2	c.881T>C	p.Phe294Ser	missense_variant	Exon 9 of 14		NP_001166924.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TFCP2	ENST00000257915.10	c.1034T>C	p.Phe345Ser	missense_variant	Exon 10 of 15	1	NM_005653.5	ENSP00000257915.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 16, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1034T>C (p.F345S) alteration is located in exon 10 (coding exon 10) of the TFCP2 gene. This alteration results from a T to C substitution at nucleotide position 1034, causing the phenylalanine (F) at amino acid position 345 to be replaced by a serine (S). 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	0.95
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D;.;T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.032	D
MetaRNN	Uncertain	0.68	D;D;D
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.5	M;.;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-5.0	D;D;D
REVEL	Benign	0.23
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.028	D;D;D
Polyphen		0.33	B;P;.
Vest4		0.60
MutPred		0.53		Gain of catalytic residue at R341 (P = 0.001);.;.;
MVP		0.72
MPC		1.5
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.73
gMVP		0.90

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-51497479;