NM_003722.5:c.62+24867G>T

Variant names:

• chr3-189656444-G-T
• rs1920245
• NM_003722.5:c.62+24867G>T

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+24867G>T 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 151,870 control chromosomes in the GnomAD database, including 16,079 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.44 (16079 hom., cov: 32)
• Consequence: TP63 NM_003722.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.79
• Publications: 1 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=-0.97).
• BP6: Variant 3-189656444-G-T is Benign according to our data. Variant chr3-189656444-G-T is described in ClinVar as Benign. ClinVar VariationId is 1241847.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.576 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+24867G>T		intron	N/A	NP_003713.3
	TP63	NM_001329964.2		c.56+59206G>T		intron	N/A	NP_001316893.1
	TP63	NM_001329148.2		c.62+24867G>T		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+24867G>T		intron	N/A	ENSP00000264731.3	Q9H3D4-1
	TP63	ENST00000440651.6	TSL:1	c.62+24867G>T		intron	N/A	ENSP00000394337.2	Q9H3D4-11
	TP63	ENST00000392460.7	TSL:1	c.62+24867G>T		intron	N/A	ENSP00000376253.3	Q9H3D4-3

Frequencies

GnomAD3 genomes AF: 0.440 AC: 66762 AN: 151752 Hom.: 16060 Cov.: 32

Gnomad AFR AF: 0.245

Gnomad AMI AF: 0.351

Gnomad AMR AF: 0.586

Gnomad ASJ AF: 0.526

Gnomad EAS AF: 0.273

Gnomad SAS AF: 0.512

Gnomad FIN AF: 0.463

Gnomad MID AF: 0.686

Gnomad NFE AF: 0.523

Gnomad OTH AF: 0.506

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

GnomAD4 genome AF: 0.440 AC: 66811 AN: 151870 Hom.: 16079 Cov.: 32 AF XY: 0.442 AC XY: 32778 AN XY: 74202

African (AFR) AF: 0.245 AC: 10170 AN: 41454

American (AMR) AF: 0.587 AC: 8939 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.526 AC: 1825 AN: 3468

East Asian (EAS) AF: 0.273 AC: 1412 AN: 5164

South Asian (SAS) AF: 0.512 AC: 2462 AN: 4808

European-Finnish (FIN) AF: 0.463 AC: 4879 AN: 10540

Middle Eastern (MID) AF: 0.690 AC: 200 AN: 290

European-Non Finnish (NFE) AF: 0.523 AC: 35528 AN: 67882

Other (OTH) AF: 0.509 AC: 1077 AN: 2114

Alfa AF: 0.472 Hom.: 2286

Bravo AF: 0.441

Asia WGS AF: 0.407 AC: 1407 AN: 3470

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	-0.97
CADD	Benign	0.39
DANN	Benign	0.47
PhyloP100		-2.8
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: rs1920245; hg19: chr3-189374233;