rs6790167

Variant names:

• chr3-189869485-A-G
• rs6790167
• NM_003722.5:c.1212+79A>G

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.1212+79A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.499 in 1,274,402 control chromosomes in the GnomAD database, including 162,496 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (22092 hom., cov: 30)
  • Exomes 𝑓: 0.50 (140404 hom.)
• Consequence: TP63 NM_003722.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.760
• Publications: 16 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=-0.89).
• BP6: Variant 3-189869485-A-G is Benign according to our data. Variant chr3-189869485-A-G is described in ClinVar as Benign. ClinVar VariationId is 1232095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.661 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.1212+79A>G		intron	N/A	NP_003713.3
	TP63	NM_001114980.2	MANE Plus Clinical	c.930+79A>G		intron	N/A	NP_001108452.1	Q9H3D4-2
	TP63	NM_001329964.2		c.1206+79A>G		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.1212+79A>G		intron	N/A	ENSP00000264731.3	Q9H3D4-1
	TP63	ENST00000354600.10	TSL:1 MANE Plus Clinical	c.930+79A>G		intron	N/A	ENSP00000346614.5	Q9H3D4-2
	TP63	ENST00000440651.6	TSL:1	c.1200+79A>G		intron	N/A	ENSP00000394337.2	Q9H3D4-11

Frequencies

GnomAD3 genomes AF: 0.530 AC: 80408 AN: 151790 Hom.: 22072 Cov.: 30

Gnomad AFR AF: 0.667

Gnomad AMI AF: 0.465

Gnomad AMR AF: 0.445

Gnomad ASJ AF: 0.509

Gnomad EAS AF: 0.395

Gnomad SAS AF: 0.393

Gnomad FIN AF: 0.403

Gnomad MID AF: 0.682

Gnomad NFE AF: 0.505

Gnomad OTH AF: 0.556

GnomAD4 exome AF: 0.495 AC: 555891 AN: 1122494 Hom.: 140404 AF XY: 0.491 AC XY: 279916 AN XY: 569828

African (AFR) AF: 0.677 AC: 17885 AN: 26434

American (AMR) AF: 0.383 AC: 14613 AN: 38194

Ashkenazi Jewish (ASJ) AF: 0.501 AC: 11790 AN: 23524

East Asian (EAS) AF: 0.422 AC: 15263 AN: 36186

South Asian (SAS) AF: 0.393 AC: 29610 AN: 75252

European-Finnish (FIN) AF: 0.402 AC: 19508 AN: 48486

Middle Eastern (MID) AF: 0.604 AC: 3076 AN: 5090

European-Non Finnish (NFE) AF: 0.511 AC: 419397 AN: 820418

Other (OTH) AF: 0.506 AC: 24749 AN: 48910

GnomAD4 genome AF: 0.530 AC: 80467 AN: 151908 Hom.: 22092 Cov.: 30 AF XY: 0.520 AC XY: 38626 AN XY: 74252

African (AFR) AF: 0.667 AC: 27655 AN: 41450

American (AMR) AF: 0.444 AC: 6774 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.509 AC: 1766 AN: 3470

East Asian (EAS) AF: 0.395 AC: 2024 AN: 5128

South Asian (SAS) AF: 0.394 AC: 1897 AN: 4812

European-Finnish (FIN) AF: 0.403 AC: 4249 AN: 10546

Middle Eastern (MID) AF: 0.671 AC: 196 AN: 292

European-Non Finnish (NFE) AF: 0.505 AC: 34317 AN: 67940

Other (OTH) AF: 0.554 AC: 1166 AN: 2106

Alfa AF: 0.520 Hom.: 27635

Bravo AF: 0.541

Asia WGS AF: 0.390 AC: 1361 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.38
DANN	Benign	0.40
PhyloP100		-0.76
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: rs6790167; hg19: chr3-189587274;