rs9853796

Variant names:

• chr3-189656853-G-C
• rs9853796
• NM_003722.5:c.62+25276G>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003722.5(TP63):​c.62+25276G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.44 in 151,762 control chromosomes in the GnomAD database, including 16,076 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.44 (16076 hom., cov: 31)
• Consequence: TP63 NM_003722.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.370
• Publications: 0 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: Orphanet, G2P
• ankyloblepharon-ectodermal defects-cleft lip/palate syndrome

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

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

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

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

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BP6: Variant 3-189656853-G-C is Benign according to our data. Variant chr3-189656853-G-C is described in ClinVar as Benign. ClinVar VariationId is 1228444.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.577 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003722.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP63	NM_003722.5	MANE Select	c.62+25276G>C		intron	N/A	NP_003713.3
	TP63	NM_001329964.2		c.56+59615G>C		intron	N/A	NP_001316893.1
	TP63	NM_001329148.2		c.62+25276G>C		intron	N/A	NP_001316077.1	A0A0S2Z4N6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP63	ENST00000264731.8	TSL:1 MANE Select	c.62+25276G>C		intron	N/A	ENSP00000264731.3	Q9H3D4-1
	TP63	ENST00000440651.6	TSL:1	c.62+25276G>C		intron	N/A	ENSP00000394337.2	Q9H3D4-11
	TP63	ENST00000392460.7	TSL:1	c.62+25276G>C		intron	N/A	ENSP00000376253.3	Q9H3D4-3

Frequencies

GnomAD3 genomes AF: 0.440 AC: 66733 AN: 151644 Hom.: 16057 Cov.: 31

Gnomad AFR AF: 0.245

Gnomad AMI AF: 0.352

Gnomad AMR AF: 0.586

Gnomad ASJ AF: 0.526

Gnomad EAS AF: 0.273

Gnomad SAS AF: 0.513

Gnomad FIN AF: 0.463

Gnomad MID AF: 0.688

Gnomad NFE AF: 0.524

Gnomad OTH AF: 0.503

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.440 AC: 66782 AN: 151762 Hom.: 16076 Cov.: 31 AF XY: 0.442 AC XY: 32751 AN XY: 74140

African (AFR) AF: 0.245 AC: 10169 AN: 41430

American (AMR) AF: 0.587 AC: 8941 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.526 AC: 1820 AN: 3462

East Asian (EAS) AF: 0.273 AC: 1412 AN: 5166

South Asian (SAS) AF: 0.513 AC: 2468 AN: 4810

European-Finnish (FIN) AF: 0.463 AC: 4866 AN: 10516

Middle Eastern (MID) AF: 0.692 AC: 202 AN: 292

European-Non Finnish (NFE) AF: 0.524 AC: 35517 AN: 67830

Other (OTH) AF: 0.507 AC: 1067 AN: 2106

Alfa AF: 0.481 Hom.: 2253

Bravo AF: 0.441

Asia WGS AF: 0.408 AC: 1414 AN: 3474

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.2
DANN	Benign	0.50
PhyloP100		-0.37
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs9853796; hg19: chr3-189374642;