chr1-3723396-A-G

Position:

• chr1-3723396-A-G

Variant summary

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

The NM_005427.4(TP73):​c.659A>G​(p.Asn220Ser) variant causes a missense change. 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: TP73 NM_005427.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.14

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 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/exons	MANE	UniProt
TP73	NM_005427.4	c.659A>G	p.Asn220Ser	missense_variant	6/14	ENST00000378295.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP73	ENST00000378295.9	c.659A>G	p.Asn220Ser	missense_variant	6/14	1	NM_005427.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 04, 2024

The c.659A>G (p.N220S) alteration is located in exon 6 (coding exon 5) of the TP73 gene. This alteration results from a A to G substitution at nucleotide position 659, causing the asparagine (N) at amino acid position 220 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	Benign	0.10
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.92	D;.;.;.;.;.;.;.;T;.;.
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.090
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;.;.;D;D;D;D
M_CAP	Pathogenic	0.58	D
MetaRNN	Uncertain	0.56	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Benign	1.5	L;L;L;L;L;L;L;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.6	D;.;D;D;D;.;.;D;D;D;D
REVEL	Uncertain	0.55
Sift	Uncertain	0.025	D;.;T;T;T;.;.;T;T;T;T
Sift4G	Benign	0.12	T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.027	B;.;B;.;.;.;.;B;.;B;.
Vest4		0.34
MutPred		0.70		Gain of glycosylation at N220 (P = 0.0637);Gain of glycosylation at N220 (P = 0.0637);Gain of glycosylation at N220 (P = 0.0637);Gain of glycosylation at N220 (P = 0.0637);Gain of glycosylation at N220 (P = 0.0637);Gain of glycosylation at N220 (P = 0.0637);Gain of glycosylation at N220 (P = 0.0637);.;.;.;.;
MVP		0.91
MPC		0.86
ClinPred		0.87	D
GERP RS		4.0
Varity_R		0.46
gMVP		0.64

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: rs1641258056; hg19: chr1-3639960;