3-189868841-C-G

Variant names:

• chr3-189868841-C-G
• rs16864880
• NM_003722.5:c.1129+125C>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.1129+125C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.156 in 1,482,662 control chromosomes in the GnomAD database, including 19,150 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1507 hom., cov: 32)
  • Exomes 𝑓: 0.16 (17643 hom.)
• Consequence: TP63 NM_003722.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.294
• Publications: 7 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: G2P, Orphanet
• ankyloblepharon-ectodermal defects-cleft lip/palate syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• limb-mammary syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• Rapp-Hodgkin syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• premature ovarian failure 21

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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=-0.86).
• BP6: Variant 3-189868841-C-G is Benign according to our data. Variant chr3-189868841-C-G is described in ClinVar as Benign. ClinVar VariationId is 1238951.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.2 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP63	NM_003722.5	MANE Select	c.1129+125C>G		intron	N/A	NP_003713.3
	TP63	NM_001114980.2	MANE Plus Clinical	c.847+125C>G		intron	N/A	NP_001108452.1
	TP63	NM_001329964.2		c.1123+125C>G		intron	N/A	NP_001316893.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP63	ENST00000264731.8	TSL:1 MANE Select	c.1129+125C>G		intron	N/A	ENSP00000264731.3
	TP63	ENST00000354600.10	TSL:1 MANE Plus Clinical	c.847+125C>G		intron	N/A	ENSP00000346614.5
	TP63	ENST00000440651.6	TSL:1	c.1117+137C>G		intron	N/A	ENSP00000394337.2

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19164 AN: 152006 Hom.: 1508 Cov.: 32

Gnomad AFR AF: 0.0488

Gnomad AMI AF: 0.0562

Gnomad AMR AF: 0.111

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.163

Gnomad SAS AF: 0.211

Gnomad FIN AF: 0.162

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.162

Gnomad OTH AF: 0.122

GnomAD4 exome AF: 0.159 AC: 211559 AN: 1330536 Hom.: 17643 AF XY: 0.162 AC XY: 108377 AN XY: 668632

African (AFR) AF: 0.0407 AC: 1253 AN: 30788

American (AMR) AF: 0.0853 AC: 3762 AN: 44126

Ashkenazi Jewish (ASJ) AF: 0.149 AC: 3754 AN: 25186

East Asian (EAS) AF: 0.167 AC: 6475 AN: 38768

South Asian (SAS) AF: 0.220 AC: 18179 AN: 82730

European-Finnish (FIN) AF: 0.155 AC: 7888 AN: 50870

Middle Eastern (MID) AF: 0.157 AC: 821 AN: 5238

European-Non Finnish (NFE) AF: 0.161 AC: 160858 AN: 996994

Other (OTH) AF: 0.153 AC: 8569 AN: 55836

GnomAD4 genome AF: 0.126 AC: 19159 AN: 152126 Hom.: 1507 Cov.: 32 AF XY: 0.127 AC XY: 9420 AN XY: 74388

African (AFR) AF: 0.0487 AC: 2024 AN: 41518

American (AMR) AF: 0.110 AC: 1686 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 523 AN: 3470

East Asian (EAS) AF: 0.163 AC: 846 AN: 5176

South Asian (SAS) AF: 0.211 AC: 1015 AN: 4818

European-Finnish (FIN) AF: 0.162 AC: 1716 AN: 10574

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.162 AC: 11002 AN: 67976

Other (OTH) AF: 0.120 AC: 252 AN: 2108

Alfa AF: 0.0540 Hom.: 80

Bravo AF: 0.115

Asia WGS AF: 0.191 AC: 666 AN: 3478

ClinVar

ClinVar submissions as Germline

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	-0.86
CADD	Benign	6.1
DANN	Benign	0.50
PhyloP100		-0.29
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs16864880; hg19: chr3-189586630; COSMIC: COSV53207418; COSMIC: COSV53207418;