NM_005427.4:c.640C>T

Variant names:

• chr1-3723377-C-T
• rs1031408044
• NM_005427.4:c.640C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_005427.4(TP73):​c.640C>T​(p.Leu214Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000959 in 1,460,336 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: 31)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: TP73 NM_005427.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.06

Genes affected

TP73 (HGNC:12003): (tumor protein p73) This gene encodes a member of the p53 family of transcription factors involved in cellular responses to stress and development. It maps to a region on chromosome 1p36 that is frequently deleted in neuroblastoma and other tumors, and thought to contain multiple tumor suppressor genes. The demonstration that this gene is monoallelically expressed (likely from the maternal allele), supports the notion that it is a candidate gene for neuroblastoma. Many transcript variants resulting from alternative splicing and/or use of alternate promoters have been found for this gene, but the biological validity and the full-length nature of some variants have not been determined. [provided by RefSeq, Feb 2011]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP73	NM_005427.4	c.640C>T	p.Leu214Phe	missense_variant	Exon 6 of 14	ENST00000378295.9	NP_005418.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP73	ENST00000378295.9	c.640C>T	p.Leu214Phe	missense_variant	Exon 6 of 14	1	NM_005427.4	ENSP00000367545.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000959 AC: 14 AN: 1460336 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 726454

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: 0.0000117

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Sep 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.640C>T (p.L214F) alteration is located in exon 6 (coding exon 5) of the TP73 gene. This alteration results from a C to T substitution at nucleotide position 640, causing the leucine (L) at amino acid position 214 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	0.96
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;.;.;.;.;.;.;.;T;.;.
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;.;.;D;D;D;D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Benign	1.7	L;L;L;L;L;L;L;.;.;.;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.8	D;.;D;D;D;.;.;D;D;D;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.029	D;.;D;D;D;.;.;D;D;D;D
Sift4G	Benign	0.10	T;T;T;T;T;T;T;T;T;T;T
Polyphen		1.0	D;.;P;.;.;.;.;D;.;D;.
Vest4		0.72
MutPred		0.83		Gain of catalytic residue at L214 (P = 0.1244);Gain of catalytic residue at L214 (P = 0.1244);Gain of catalytic residue at L214 (P = 0.1244);Gain of catalytic residue at L214 (P = 0.1244);Gain of catalytic residue at L214 (P = 0.1244);Gain of catalytic residue at L214 (P = 0.1244);Gain of catalytic residue at L214 (P = 0.1244);.;.;.;.;
MVP		0.92
MPC		2.3
ClinPred		0.99	D
GERP RS		3.0
Varity_R		0.54
gMVP		0.77

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: rs1031408044; hg19: chr1-3639941;