19-54110116-G-T

Variant names:

• chr19-54110116-G-T
• rs1051140983
• NM_013342.4:c.288C>A

Variant summary

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

The NM_013342.4(TFPT):​c.288C>A​(p.Asn96Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: TFPT NM_013342.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.20

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

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
TFPT	NM_013342.4	c.288C>A	p.Asn96Lys	missense_variant	Exon 3 of 6	ENST00000391759.6	NP_037474.1
TFPT	NM_001321792.2	c.261C>A	p.Asn87Lys	missense_variant	Exon 3 of 6		NP_001308721.1
TFPT	XM_005278261.2	c.-73C>A		5_prime_UTR_variant	Exon 2 of 5		XP_005278318.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TFPT	ENST00000391759.6	c.288C>A	p.Asn96Lys	missense_variant	Exon 3 of 6	1	NM_013342.4	ENSP00000375639.1
TFPT	ENST00000391758.5	c.261C>A	p.Asn87Lys	missense_variant	Exon 3 of 6	1		ENSP00000375638.1
TFPT	ENST00000391757.1	c.288C>A	p.Asn96Lys	missense_variant	Exon 3 of 6	5		ENSP00000375637.1
TFPT	ENST00000420715.6	n.283-1721C>A		intron_variant	Intron 2 of 4	5		ENSP00000395180.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251296 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135848

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461856 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 727228

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 06, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.288C>A (p.N96K) alteration is located in exon 3 (coding exon 3) of the TFPT gene. This alteration results from a C to A substitution at nucleotide position 288, causing the asparagine (N) at amino acid position 96 to be replaced by a lysine (K). 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	1.0
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	11
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D;.;.
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.73	.;T;T
M_CAP	Benign	0.048	D
MetaRNN	Uncertain	0.73	D;D;D
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.1	M;.;.
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-5.2	D;D;D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0040	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.97	D;.;.
Vest4		0.88
MutPred		0.42		Gain of methylation at N96 (P = 0.0092);.;Gain of methylation at N96 (P = 0.0092);
MVP		0.26
MPC		0.084
ClinPred		0.94	D
GERP RS		-4.4
Varity_R		0.79
gMVP		0.89

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

Other links and lift over

dbSNP: rs1051140983; hg19: chr19-54613499; COSMIC: COSV57837749; COSMIC: COSV57837749;