3-189873035-G-C

Variant names:

• chr3-189873035-G-C
• rs9840359
• NM_003722.5:c.1349+40G>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.1349+40G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.529 in 1,612,994 control chromosomes in the GnomAD database, including 229,603 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (23235 hom., cov: 32)
  • Exomes 𝑓: 0.53 (206368 hom.)
• Consequence: TP63 NM_003722.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.987
• Publications: 11 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=-0.84).
• BP6: Variant 3-189873035-G-C is Benign according to our data. Variant chr3-189873035-G-C is described in ClinVar as Benign. ClinVar VariationId is 259125.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.636 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.1349+40G>C		intron	N/A	NP_003713.3
	TP63	NM_001114980.2	MANE Plus Clinical	c.1067+40G>C		intron	N/A	NP_001108452.1	Q9H3D4-2
	TP63	NM_001329964.2		c.1343+40G>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.1349+40G>C		intron	N/A	ENSP00000264731.3	Q9H3D4-1
	TP63	ENST00000354600.10	TSL:1 MANE Plus Clinical	c.1067+40G>C		intron	N/A	ENSP00000346614.5	Q9H3D4-2
	TP63	ENST00000440651.6	TSL:1	c.1337+40G>C		intron	N/A	ENSP00000394337.2	Q9H3D4-11

Frequencies

GnomAD3 genomes AF: 0.546 AC: 82935 AN: 151806 Hom.: 23225 Cov.: 32

Gnomad AFR AF: 0.643

Gnomad AMI AF: 0.486

Gnomad AMR AF: 0.468

Gnomad ASJ AF: 0.457

Gnomad EAS AF: 0.346

Gnomad SAS AF: 0.377

Gnomad FIN AF: 0.484

Gnomad MID AF: 0.706

Gnomad NFE AF: 0.546

Gnomad OTH AF: 0.564

GnomAD2 exomes AF: 0.487 AC: 121992 AN: 250592 AF XY: 0.487

Gnomad AFR exome AF: 0.647

Gnomad AMR exome AF: 0.386

Gnomad ASJ exome AF: 0.453

Gnomad EAS exome AF: 0.359

Gnomad FIN exome AF: 0.476

Gnomad NFE exome AF: 0.550

Gnomad OTH exome AF: 0.516

GnomAD4 exome AF: 0.527 AC: 770307 AN: 1461070 Hom.: 206368 Cov.: 40 AF XY: 0.523 AC XY: 380473 AN XY: 726882

African (AFR) AF: 0.649 AC: 21723 AN: 33464

American (AMR) AF: 0.396 AC: 17702 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.457 AC: 11930 AN: 26126

East Asian (EAS) AF: 0.373 AC: 14796 AN: 39688

South Asian (SAS) AF: 0.375 AC: 32333 AN: 86236

European-Finnish (FIN) AF: 0.488 AC: 26037 AN: 53402

Middle Eastern (MID) AF: 0.597 AC: 3440 AN: 5760

European-Non Finnish (NFE) AF: 0.549 AC: 610620 AN: 1111308

Other (OTH) AF: 0.526 AC: 31726 AN: 60370

GnomAD4 genome AF: 0.546 AC: 82973 AN: 151924 Hom.: 23235 Cov.: 32 AF XY: 0.536 AC XY: 39799 AN XY: 74242

African (AFR) AF: 0.643 AC: 26592 AN: 41384

American (AMR) AF: 0.467 AC: 7143 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.457 AC: 1584 AN: 3468

East Asian (EAS) AF: 0.346 AC: 1785 AN: 5162

South Asian (SAS) AF: 0.378 AC: 1818 AN: 4814

European-Finnish (FIN) AF: 0.484 AC: 5108 AN: 10560

Middle Eastern (MID) AF: 0.687 AC: 202 AN: 294

European-Non Finnish (NFE) AF: 0.546 AC: 37119 AN: 67938

Other (OTH) AF: 0.558 AC: 1179 AN: 2112

Alfa AF: 0.445 Hom.: 2119

Bravo AF: 0.554

Asia WGS AF: 0.350 AC: 1223 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.1
DANN	Benign	0.48
PhyloP100		0.99
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: rs9840359; hg19: chr3-189590824; COSMIC: COSV53199343;