rs9662633

Variant names:

• chr1-3732998-G-A
• rs9662633
• NM_005427.4:c.1830G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_005427.4(TP73):​c.1830G>A​(p.Ala610Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0492 in 1,579,402 control chromosomes in the GnomAD database, including 3,138 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.081 (802 hom., cov: 33)
  • Exomes 𝑓: 0.046 (2336 hom.)
• Consequence: TP73 NM_005427.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.97
• Publications: 24 publications found

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]

TP73 Gene-Disease associations (from GenCC):

• ciliary dyskinesia, primary, 47, and lissencephaly

  Inheritance: AR Classification: STRONG Submitted by: ClinGen, G2P

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP7: Synonymous conserved (PhyloP=-3.97 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.211 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP73	NM_005427.4	c.1830G>A	p.Ala610Ala	synonymous_variant	Exon 14 of 14	ENST00000378295.9	NP_005418.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP73	ENST00000378295.9	c.1830G>A	p.Ala610Ala	synonymous_variant	Exon 14 of 14	1	NM_005427.4	ENSP00000367545.4

Frequencies

GnomAD3 genomes AF: 0.0809 AC: 12311 AN: 152082 Hom.: 796 Cov.: 33

Gnomad AFR AF: 0.160

Gnomad AMI AF: 0.0921

Gnomad AMR AF: 0.0403

Gnomad ASJ AF: 0.0487

Gnomad EAS AF: 0.223

Gnomad SAS AF: 0.0524

Gnomad FIN AF: 0.0515

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0400

Gnomad OTH AF: 0.0606

GnomAD2 exomes AF: 0.0643 AC: 11998 AN: 186522 AF XY: 0.0618

Gnomad AFR exome AF: 0.167

Gnomad AMR exome AF: 0.0260

Gnomad ASJ exome AF: 0.0533

Gnomad EAS exome AF: 0.232

Gnomad FIN exome AF: 0.0539

Gnomad NFE exome AF: 0.0427

Gnomad OTH exome AF: 0.0520

GnomAD4 exome AF: 0.0458 AC: 65402 AN: 1427202 Hom.: 2336 Cov.: 31 AF XY: 0.0455 AC XY: 32198 AN XY: 708100

African (AFR) AF: 0.164 AC: 5342 AN: 32590

American (AMR) AF: 0.0278 AC: 1147 AN: 41192

Ashkenazi Jewish (ASJ) AF: 0.0511 AC: 1308 AN: 25602

East Asian (EAS) AF: 0.162 AC: 6115 AN: 37662

South Asian (SAS) AF: 0.0487 AC: 4033 AN: 82844

European-Finnish (FIN) AF: 0.0573 AC: 2497 AN: 43604

Middle Eastern (MID) AF: 0.0578 AC: 331 AN: 5726

European-Non Finnish (NFE) AF: 0.0372 AC: 40911 AN: 1098798

Other (OTH) AF: 0.0628 AC: 3718 AN: 59184

GnomAD4 genome AF: 0.0812 AC: 12353 AN: 152200 Hom.: 802 Cov.: 33 AF XY: 0.0814 AC XY: 6056 AN XY: 74420

African (AFR) AF: 0.161 AC: 6666 AN: 41506

American (AMR) AF: 0.0403 AC: 616 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0487 AC: 169 AN: 3468

East Asian (EAS) AF: 0.222 AC: 1147 AN: 5170

South Asian (SAS) AF: 0.0516 AC: 249 AN: 4828

European-Finnish (FIN) AF: 0.0515 AC: 547 AN: 10614

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0400 AC: 2719 AN: 67996

Other (OTH) AF: 0.0643 AC: 136 AN: 2116

Alfa AF: 0.0467 Hom.: 506

Bravo AF: 0.0845

Asia WGS AF: 0.130 AC: 451 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.8
DANN	Benign	0.95
PhyloP100		-4.0
Mutation Taster		=99/1	polymorphism (auto)

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: rs9662633; hg19: chr1-3649562; COSMIC: COSV60698394; COSMIC: COSV60698394;