19-54110111-C-G

Variant names:

• chr19-54110111-C-G
• rs774272913
• NM_013342.4:c.293G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_013342.4(TFPT):​c.293G>C​(p.Arg98Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R98Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TFPT NM_013342.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.19
• Publications: 0 publications found

Genes affected

TFPT (HGNC:13630): (TCF3 fusion partner) Predicted to enable DNA binding activity and protein kinase binding activity. Involved in apoptotic signaling pathway. Located in nucleoplasm. Part of Ino80 complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.762

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013342.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFPT	NM_013342.4	MANE Select	c.293G>C	p.Arg98Pro	missense	Exon 3 of 6	NP_037474.1	P0C1Z6-1
	TFPT	NM_001321792.2		c.266G>C	p.Arg89Pro	missense	Exon 3 of 6	NP_001308721.1	P0C1Z6-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFPT	ENST00000391759.6	TSL:1 MANE Select	c.293G>C	p.Arg98Pro	missense	Exon 3 of 6	ENSP00000375639.1	P0C1Z6-1
	TFPT	ENST00000391758.5	TSL:1	c.266G>C	p.Arg89Pro	missense	Exon 3 of 6	ENSP00000375638.1	P0C1Z6-2
	TFPT	ENST00000911297.1		c.293G>C	p.Arg98Pro	missense	Exon 3 of 6	ENSP00000581356.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461864 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727236

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.86	D
M_CAP	Benign	0.023	T
MetaRNN	Pathogenic	0.76	D
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	2.0	M
PhyloP100		5.2
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-4.9	D
REVEL	Benign	0.21
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.87	P
Vest4		0.91
MutPred		0.30		Loss of MoRF binding (P = 0.0046)
MVP		0.61
MPC		0.37
ClinPred		0.98	D
GERP RS		4.5
Varity_R		0.92
gMVP		0.74
Mutation Taster		=61/39	polymorphism

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

Other links and lift over

dbSNP: rs774272913; hg19: chr19-54613494;