chr3-189631458-A-T

Variant names:

• chr3-189631458-A-T
• rs28673064
• NM_003722.5:c.-58A>T

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.-58A>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.479 in 1,608,672 control chromosomes in the GnomAD database, including 187,736 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (16347 hom., cov: 33)
  • Exomes 𝑓: 0.48 (171389 hom.)
• Consequence: TP63 NM_003722.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.26
• Publications: 19 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, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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)
• 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=-0.55).
• BP6: Variant 3-189631458-A-T is Benign according to our data. Variant chr3-189631458-A-T is described in ClinVar as Benign. ClinVar VariationId is 344379.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.709 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.-58A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 14	NP_003713.3
	TP63	NM_003722.5	MANE Select	c.-58A>T		5_prime_UTR	Exon 1 of 14	NP_003713.3
	TP63	NM_001329148.2		c.-58A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 14	NP_001316077.1	A0A0S2Z4N6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP63	ENST00000264731.8	TSL:1 MANE Select	c.-58A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 14	ENSP00000264731.3	Q9H3D4-1
	TP63	ENST00000264731.8	TSL:1 MANE Select	c.-58A>T		5_prime_UTR	Exon 1 of 14	ENSP00000264731.3	Q9H3D4-1
	TP63	ENST00000486398.1	TSL:3	n.43A>T		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes AF: 0.457 AC: 69439 AN: 151898 Hom.: 16344 Cov.: 33

Gnomad AFR AF: 0.399

Gnomad AMI AF: 0.649

Gnomad AMR AF: 0.375

Gnomad ASJ AF: 0.452

Gnomad EAS AF: 0.728

Gnomad SAS AF: 0.490

Gnomad FIN AF: 0.533

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.476

Gnomad OTH AF: 0.424

GnomAD4 exome AF: 0.482 AC: 701754 AN: 1456656 Hom.: 171389 Cov.: 39 AF XY: 0.482 AC XY: 349392 AN XY: 724792

African (AFR) AF: 0.398 AC: 13227 AN: 33252

American (AMR) AF: 0.336 AC: 14961 AN: 44510

Ashkenazi Jewish (ASJ) AF: 0.448 AC: 11630 AN: 25986

East Asian (EAS) AF: 0.740 AC: 29221 AN: 39484

South Asian (SAS) AF: 0.490 AC: 42142 AN: 86038

European-Finnish (FIN) AF: 0.524 AC: 27629 AN: 52694

Middle Eastern (MID) AF: 0.371 AC: 2126 AN: 5738

European-Non Finnish (NFE) AF: 0.480 AC: 531894 AN: 1108862

Other (OTH) AF: 0.481 AC: 28924 AN: 60092

GnomAD4 genome AF: 0.457 AC: 69460 AN: 152016 Hom.: 16347 Cov.: 33 AF XY: 0.460 AC XY: 34173 AN XY: 74300

African (AFR) AF: 0.398 AC: 16515 AN: 41454

American (AMR) AF: 0.374 AC: 5717 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.452 AC: 1571 AN: 3472

East Asian (EAS) AF: 0.728 AC: 3758 AN: 5162

South Asian (SAS) AF: 0.490 AC: 2364 AN: 4826

European-Finnish (FIN) AF: 0.533 AC: 5638 AN: 10570

Middle Eastern (MID) AF: 0.296 AC: 87 AN: 294

European-Non Finnish (NFE) AF: 0.476 AC: 32328 AN: 67946

Other (OTH) AF: 0.421 AC: 890 AN: 2112

Alfa AF: 0.313 Hom.: 776

Bravo AF: 0.443

Asia WGS AF: 0.570 AC: 1985 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3 (1)
-	-	1	Orofacial cleft 8 (1)
-	-	1	TP63-Related Spectrum Disorders (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	17
DANN	Benign	0.89
PhyloP100		4.3
PromoterAI		0.025	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs28673064; hg19: chr3-189349247; COSMIC: COSV53195405; COSMIC: COSV53195405;