chr3-189869302-A-G

Variant names:

• chr3-189869302-A-G
• rs6789961
• NM_003722.5:c.1130-22A>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.1130-22A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.234 in 1,607,668 control chromosomes in the GnomAD database, including 50,107 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (9766 hom., cov: 32)
  • Exomes 𝑓: 0.23 (40341 hom.)
• Consequence: TP63 NM_003722.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.14
• Publications: 13 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=-0.61).
• BP6: Variant 3-189869302-A-G is Benign according to our data. Variant chr3-189869302-A-G is described in ClinVar as Benign. ClinVar VariationId is 259124.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.577 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.1130-22A>G		intron	N/A	NP_003713.3
	TP63	NM_001114980.2	MANE Plus Clinical	c.848-22A>G		intron	N/A	NP_001108452.1	Q9H3D4-2
	TP63	NM_001329964.2		c.1124-22A>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.1130-22A>G		intron	N/A	ENSP00000264731.3	Q9H3D4-1
	TP63	ENST00000354600.10	TSL:1 MANE Plus Clinical	c.848-22A>G		intron	N/A	ENSP00000346614.5	Q9H3D4-2
	TP63	ENST00000440651.6	TSL:1	c.1118-22A>G		intron	N/A	ENSP00000394337.2	Q9H3D4-11

Frequencies

GnomAD3 genomes AF: 0.316 AC: 48059 AN: 151942 Hom.: 9745 Cov.: 32

Gnomad AFR AF: 0.583

Gnomad AMI AF: 0.224

Gnomad AMR AF: 0.214

Gnomad ASJ AF: 0.262

Gnomad EAS AF: 0.151

Gnomad SAS AF: 0.190

Gnomad FIN AF: 0.214

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.218

Gnomad OTH AF: 0.318

GnomAD2 exomes AF: 0.224 AC: 56225 AN: 250938 AF XY: 0.221

Gnomad AFR exome AF: 0.593

Gnomad AMR exome AF: 0.135

Gnomad ASJ exome AF: 0.265

Gnomad EAS exome AF: 0.156

Gnomad FIN exome AF: 0.210

Gnomad NFE exome AF: 0.219

Gnomad OTH exome AF: 0.232

GnomAD4 exome AF: 0.226 AC: 328802 AN: 1455606 Hom.: 40341 Cov.: 30 AF XY: 0.224 AC XY: 162432 AN XY: 724606

African (AFR) AF: 0.600 AC: 19996 AN: 33332

American (AMR) AF: 0.146 AC: 6506 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.269 AC: 7021 AN: 26092

East Asian (EAS) AF: 0.150 AC: 5945 AN: 39642

South Asian (SAS) AF: 0.186 AC: 15983 AN: 86140

European-Finnish (FIN) AF: 0.207 AC: 11067 AN: 53388

Middle Eastern (MID) AF: 0.348 AC: 2005 AN: 5758

European-Non Finnish (NFE) AF: 0.222 AC: 245443 AN: 1106394

Other (OTH) AF: 0.247 AC: 14836 AN: 60160

GnomAD4 genome AF: 0.316 AC: 48113 AN: 152062 Hom.: 9766 Cov.: 32 AF XY: 0.311 AC XY: 23098 AN XY: 74338

African (AFR) AF: 0.583 AC: 24169 AN: 41470

American (AMR) AF: 0.213 AC: 3261 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.262 AC: 908 AN: 3472

East Asian (EAS) AF: 0.151 AC: 778 AN: 5168

South Asian (SAS) AF: 0.191 AC: 918 AN: 4816

European-Finnish (FIN) AF: 0.214 AC: 2263 AN: 10574

Middle Eastern (MID) AF: 0.435 AC: 128 AN: 294

European-Non Finnish (NFE) AF: 0.218 AC: 14824 AN: 67972

Other (OTH) AF: 0.313 AC: 660 AN: 2108

Alfa AF: 0.247 Hom.: 10984

Bravo AF: 0.330

Asia WGS AF: 0.178 AC: 617 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	-0.61
CADD	Benign	14
DANN	Benign	0.61
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs6789961; hg19: chr3-189587091; COSMIC: COSV53195425;