chr3-189886371-T-C

Variant names:

• chr3-189886371-T-C
• rs1345186
• NM_003722.5:c.1350-23T>C

Variant summary

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

The NM_003722.5(TP63):​c.1350-23T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.766 in 1,611,378 control chromosomes in the GnomAD database, including 475,797 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.74 (42417 hom., cov: 32)
  • Exomes 𝑓: 0.77 (433380 hom.)
• Consequence: TP63 NM_003722.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0850
• Publications: 18 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, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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)
• TP63-related ectodermal dysplasia spectrum with limb and orofacial malformations

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• 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=-0.88).
• BP6: Variant 3-189886371-T-C is Benign according to our data. Variant chr3-189886371-T-C is described in ClinVar as Benign. ClinVar VariationId is 259127.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.783 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.1350-23T>C		intron	N/A	NP_003713.3
	TP63	NM_001114980.2	MANE Plus Clinical	c.1068-23T>C		intron	N/A	NP_001108452.1	Q9H3D4-2
	TP63	NM_001329964.2		c.1344-23T>C		intron	N/A	NP_001316893.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP63	ENST00000264731.8	TSL:1 MANE Select	c.1350-23T>C		intron	N/A	ENSP00000264731.3	Q9H3D4-1
	TP63	ENST00000354600.10	TSL:1 MANE Plus Clinical	c.1068-23T>C		intron	N/A	ENSP00000346614.5	Q9H3D4-2
	TP63	ENST00000440651.6	TSL:1	c.1338-23T>C		intron	N/A	ENSP00000394337.2	Q9H3D4-11

Frequencies

GnomAD3 genomes AF: 0.744 AC: 113060 AN: 151954 Hom.: 42399 Cov.: 32

Gnomad AFR AF: 0.748

Gnomad AMI AF: 0.755

Gnomad AMR AF: 0.624

Gnomad ASJ AF: 0.692

Gnomad EAS AF: 0.605

Gnomad SAS AF: 0.714

Gnomad FIN AF: 0.704

Gnomad MID AF: 0.902

Gnomad NFE AF: 0.789

Gnomad OTH AF: 0.764

GnomAD2 exomes AF: 0.711 AC: 178228 AN: 250778 AF XY: 0.723

Gnomad AFR exome AF: 0.746

Gnomad AMR exome AF: 0.501

Gnomad ASJ exome AF: 0.686

Gnomad EAS exome AF: 0.598

Gnomad FIN exome AF: 0.696

Gnomad NFE exome AF: 0.789

Gnomad OTH exome AF: 0.737

GnomAD4 exome AF: 0.768 AC: 1120877 AN: 1459304 Hom.: 433380 Cov.: 41 AF XY: 0.768 AC XY: 557986 AN XY: 726078

African (AFR) AF: 0.744 AC: 24883 AN: 33438

American (AMR) AF: 0.514 AC: 22971 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.683 AC: 17837 AN: 26116

East Asian (EAS) AF: 0.635 AC: 25197 AN: 39654

South Asian (SAS) AF: 0.718 AC: 61850 AN: 86134

European-Finnish (FIN) AF: 0.703 AC: 37249 AN: 52984

Middle Eastern (MID) AF: 0.847 AC: 4880 AN: 5762

European-Non Finnish (NFE) AF: 0.793 AC: 880050 AN: 1110190

Other (OTH) AF: 0.762 AC: 45960 AN: 60318

GnomAD4 genome AF: 0.744 AC: 113118 AN: 152074 Hom.: 42417 Cov.: 32 AF XY: 0.735 AC XY: 54599 AN XY: 74318

African (AFR) AF: 0.748 AC: 31014 AN: 41482

American (AMR) AF: 0.623 AC: 9505 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.692 AC: 2401 AN: 3470

East Asian (EAS) AF: 0.606 AC: 3128 AN: 5164

South Asian (SAS) AF: 0.714 AC: 3445 AN: 4822

European-Finnish (FIN) AF: 0.704 AC: 7444 AN: 10580

Middle Eastern (MID) AF: 0.895 AC: 263 AN: 294

European-Non Finnish (NFE) AF: 0.789 AC: 53627 AN: 67974

Other (OTH) AF: 0.759 AC: 1602 AN: 2112

Alfa AF: 0.717 Hom.: 7507

Bravo AF: 0.736

Asia WGS AF: 0.655 AC: 2283 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	5.6
DANN	Benign	0.67
PhyloP100		0.085
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: rs1345186; hg19: chr3-189604160; COSMIC: COSV53208052; COSMIC: COSV53208052;