chr3-189737892-T-C

Variant names:

• chr3-189737892-T-C
• rs34875865
• NM_003722.5:c.191+24T>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.191+24T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0496 in 1,613,296 control chromosomes in the GnomAD database, including 2,544 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (197 hom., cov: 32)
  • Exomes 𝑓: 0.051 (2347 hom.)
• Consequence: TP63 NM_003722.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.761
• Publications: 3 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=-0.84).
• BP6: Variant 3-189737892-T-C is Benign according to our data. Variant chr3-189737892-T-C is described in ClinVar as Benign. ClinVar VariationId is 259131.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.058 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP63	NM_003722.5	c.191+24T>C		intron_variant	Intron 2 of 13	ENST00000264731.8	NP_003713.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP63	ENST00000264731.8	c.191+24T>C		intron_variant	Intron 2 of 13	1	NM_003722.5	ENSP00000264731.3

Frequencies

GnomAD3 genomes AF: 0.0354 AC: 5391 AN: 152100 Hom.: 197 Cov.: 32

Gnomad AFR AF: 0.00789

Gnomad AMI AF: 0.0286

Gnomad AMR AF: 0.0156

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0168

Gnomad FIN AF: 0.0557

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0595

Gnomad OTH AF: 0.0287

GnomAD2 exomes AF: 0.0379 AC: 9475 AN: 250330 AF XY: 0.0377

Gnomad AFR exome AF: 0.00727

Gnomad AMR exome AF: 0.0162

Gnomad ASJ exome AF: 0.00358

Gnomad EAS exome AF: 0.0000546

Gnomad FIN exome AF: 0.0553

Gnomad NFE exome AF: 0.0611

Gnomad OTH exome AF: 0.0385

GnomAD4 exome AF: 0.0510 AC: 74549 AN: 1461078 Hom.: 2347 Cov.: 31 AF XY: 0.0501 AC XY: 36421 AN XY: 726834

African (AFR) AF: 0.00774 AC: 259 AN: 33460

American (AMR) AF: 0.0167 AC: 745 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00452 AC: 118 AN: 26118

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39614

South Asian (SAS) AF: 0.0152 AC: 1314 AN: 86236

European-Finnish (FIN) AF: 0.0571 AC: 3045 AN: 53356

Middle Eastern (MID) AF: 0.0261 AC: 150 AN: 5758

European-Non Finnish (NFE) AF: 0.0598 AC: 66493 AN: 1111476

Other (OTH) AF: 0.0401 AC: 2423 AN: 60356

GnomAD4 genome AF: 0.0354 AC: 5392 AN: 152218 Hom.: 197 Cov.: 32 AF XY: 0.0339 AC XY: 2526 AN XY: 74436

African (AFR) AF: 0.00787 AC: 327 AN: 41544

American (AMR) AF: 0.0156 AC: 239 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.0172 AC: 83 AN: 4830

European-Finnish (FIN) AF: 0.0557 AC: 591 AN: 10604

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0595 AC: 4045 AN: 67984

Other (OTH) AF: 0.0284 AC: 60 AN: 2112

Alfa AF: 0.0542 Hom.: 426

Bravo AF: 0.0317

Asia WGS AF: 0.00808 AC: 30 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.9
DANN	Benign	0.73
PhyloP100		0.76
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs34875865; hg19: chr3-189455681;