rs9840360

Variant names:

• chr3-189873036-G-A
• rs9840360
• ENST00000460036.1:n.1214G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-189873036-G-A
• chr3-189873036-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000460036.1(TP63):​n.1214G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.206 in 1,613,004 control chromosomes in the GnomAD database, including 36,282 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5115 hom., cov: 32)
  • Exomes 𝑓: 0.20 (31167 hom.)
• Consequence: TP63 ENST00000460036.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.66
• Publications: 7 publications found

Genes affected

TP63 (HGNC:15979): (tumor protein p63) This gene encodes a member of the p53 family of transcription factors. The functional domains of p53 family proteins include an N-terminal transactivation domain, a central DNA-binding domain and an oligomerization domain. Alternative splicing of this gene and the use of alternative promoters results in multiple transcript variants encoding different isoforms that vary in their functional properties. These isoforms function during skin development and maintenance, adult stem/progenitor cell regulation, heart development and premature aging. Some isoforms have been found to protect the germline by eliminating oocytes or testicular germ cells that have suffered DNA damage. Mutations in this gene are associated with ectodermal dysplasia, and cleft lip/palate syndrome 3 (EEC3); split-hand/foot malformation 4 (SHFM4); ankyloblepharon-ectodermal defects-cleft lip/palate; ADULT syndrome (acro-dermato-ungual-lacrimal-tooth); limb-mammary syndrome; Rap-Hodgkin syndrome (RHS); and orofacial cleft 8. [provided by RefSeq, Aug 2016]

TP63 Gene-Disease associations (from GenCC):

• ADULT syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• ankyloblepharon-ectodermal defects-cleft lip/palate syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• limb-mammary syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• Rapp-Hodgkin syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• premature ovarian failure 21

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• split hand-foot malformation 4

  Inheritance: AD Classification: MODERATE Submitted by: Illumina
• EEC syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• split hand-foot malformation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 3-189873036-G-A is Benign according to our data. Variant chr3-189873036-G-A is described in ClinVar as Benign. ClinVar VariationId is 259126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.371 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000460036.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP63	NM_003722.5	MANE Select	c.1349+41G>A		intron	N/A	NP_003713.3
	TP63	NM_001114980.2	MANE Plus Clinical	c.1067+41G>A		intron	N/A	NP_001108452.1
	TP63	NM_001329964.2		c.1343+41G>A		intron	N/A	NP_001316893.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP63	ENST00000460036.1	TSL:1	n.1214G>A		non_coding_transcript_exon	Exon 8 of 8
	TP63	ENST00000264731.8	TSL:1 MANE Select	c.1349+41G>A		intron	N/A	ENSP00000264731.3
	TP63	ENST00000354600.10	TSL:1 MANE Plus Clinical	c.1067+41G>A		intron	N/A	ENSP00000346614.5

Frequencies

GnomAD3 genomes AF: 0.246 AC: 37391 AN: 151796 Hom.: 5111 Cov.: 32

Gnomad AFR AF: 0.376

Gnomad AMI AF: 0.246

Gnomad AMR AF: 0.167

Gnomad ASJ AF: 0.163

Gnomad EAS AF: 0.165

Gnomad SAS AF: 0.229

Gnomad FIN AF: 0.250

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.197

Gnomad OTH AF: 0.224

GnomAD2 exomes AF: 0.202 AC: 50518 AN: 250562 AF XY: 0.204

Gnomad AFR exome AF: 0.379

Gnomad AMR exome AF: 0.102

Gnomad ASJ exome AF: 0.159

Gnomad EAS exome AF: 0.178

Gnomad FIN exome AF: 0.242

Gnomad NFE exome AF: 0.201

Gnomad OTH exome AF: 0.202

GnomAD4 exome AF: 0.202 AC: 295645 AN: 1461090 Hom.: 31167 Cov.: 34 AF XY: 0.203 AC XY: 147836 AN XY: 726900

African (AFR) AF: 0.380 AC: 12719 AN: 33458

American (AMR) AF: 0.112 AC: 5018 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.166 AC: 4346 AN: 26132

East Asian (EAS) AF: 0.166 AC: 6589 AN: 39686

South Asian (SAS) AF: 0.222 AC: 19180 AN: 86238

European-Finnish (FIN) AF: 0.249 AC: 13322 AN: 53410

Middle Eastern (MID) AF: 0.265 AC: 1527 AN: 5752

European-Non Finnish (NFE) AF: 0.198 AC: 219873 AN: 1111328

Other (OTH) AF: 0.217 AC: 13071 AN: 60372

GnomAD4 genome AF: 0.246 AC: 37398 AN: 151914 Hom.: 5115 Cov.: 32 AF XY: 0.245 AC XY: 18167 AN XY: 74242

African (AFR) AF: 0.376 AC: 15530 AN: 41344

American (AMR) AF: 0.167 AC: 2550 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.163 AC: 567 AN: 3472

East Asian (EAS) AF: 0.165 AC: 854 AN: 5166

South Asian (SAS) AF: 0.229 AC: 1102 AN: 4820

European-Finnish (FIN) AF: 0.250 AC: 2635 AN: 10554

Middle Eastern (MID) AF: 0.282 AC: 83 AN: 294

European-Non Finnish (NFE) AF: 0.197 AC: 13386 AN: 67962

Other (OTH) AF: 0.221 AC: 467 AN: 2112

Alfa AF: 0.215 Hom.: 5676

Bravo AF: 0.246

Asia WGS AF: 0.186 AC: 646 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.018
DANN	Benign	0.50
PhyloP100		-1.7
Mutation Taster		=100/0	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: rs9840360; hg19: chr3-189590825; COSMIC: COSV53198302;