3-189886360-T-G

Variant names:

• chr3-189886360-T-G
• rs1554131
• NM_003722.5:c.1350-34T>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.1350-34T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.766 in 1,606,346 control chromosomes in the GnomAD database, including 474,367 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.74 (42393 hom., cov: 32)
  • Exomes 𝑓: 0.77 (431974 hom.)
• Consequence: TP63 NM_003722.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.91
• 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: 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=-0.91).
• BP6: Variant 3-189886360-T-G is Benign according to our data. Variant chr3-189886360-T-G is described in ClinVar as Benign. ClinVar VariationId is 259128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.783 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.1350-34T>G		intron	N/A	NP_003713.3
	TP63	NM_001114980.2	MANE Plus Clinical	c.1068-34T>G		intron	N/A	NP_001108452.1
	TP63	NM_001329964.2		c.1344-34T>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.1350-34T>G		intron	N/A	ENSP00000264731.3
	TP63	ENST00000354600.10	TSL:1 MANE Plus Clinical	c.1068-34T>G		intron	N/A	ENSP00000346614.5
	TP63	ENST00000440651.6	TSL:1	c.1338-34T>G		intron	N/A	ENSP00000394337.2

Frequencies

GnomAD3 genomes AF: 0.744 AC: 113016 AN: 151940 Hom.: 42376 Cov.: 32

Gnomad AFR AF: 0.748

Gnomad AMI AF: 0.758

Gnomad AMR AF: 0.622

Gnomad ASJ AF: 0.691

Gnomad EAS AF: 0.604

Gnomad SAS AF: 0.714

Gnomad FIN AF: 0.704

Gnomad MID AF: 0.902

Gnomad NFE AF: 0.789

Gnomad OTH AF: 0.763

GnomAD2 exomes AF: 0.710 AC: 177842 AN: 250366 AF XY: 0.722

Gnomad AFR exome AF: 0.746

Gnomad AMR exome AF: 0.501

Gnomad ASJ exome AF: 0.686

Gnomad EAS exome AF: 0.595

Gnomad FIN exome AF: 0.696

Gnomad NFE exome AF: 0.789

Gnomad OTH exome AF: 0.737

GnomAD4 exome AF: 0.768 AC: 1116942 AN: 1454288 Hom.: 431974 Cov.: 34 AF XY: 0.768 AC XY: 556275 AN XY: 723900

African (AFR) AF: 0.744 AC: 24822 AN: 33354

American (AMR) AF: 0.513 AC: 22945 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.683 AC: 17820 AN: 26092

East Asian (EAS) AF: 0.635 AC: 25145 AN: 39622

South Asian (SAS) AF: 0.718 AC: 61707 AN: 85946

European-Finnish (FIN) AF: 0.703 AC: 36985 AN: 52606

Middle Eastern (MID) AF: 0.847 AC: 4871 AN: 5754

European-Non Finnish (NFE) AF: 0.793 AC: 876821 AN: 1106040

Other (OTH) AF: 0.762 AC: 45826 AN: 60168

GnomAD4 genome AF: 0.744 AC: 113072 AN: 152058 Hom.: 42393 Cov.: 32 AF XY: 0.734 AC XY: 54586 AN XY: 74328

African (AFR) AF: 0.748 AC: 31002 AN: 41466

American (AMR) AF: 0.621 AC: 9495 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.691 AC: 2399 AN: 3470

East Asian (EAS) AF: 0.604 AC: 3119 AN: 5164

South Asian (SAS) AF: 0.714 AC: 3442 AN: 4818

European-Finnish (FIN) AF: 0.704 AC: 7447 AN: 10582

Middle Eastern (MID) AF: 0.895 AC: 263 AN: 294

European-Non Finnish (NFE) AF: 0.789 AC: 53618 AN: 67968

Other (OTH) AF: 0.758 AC: 1599 AN: 2110

Alfa AF: 0.771 Hom.: 119934

Bravo AF: 0.736

Asia WGS AF: 0.656 AC: 2285 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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.032
DANN	Benign	0.67
PhyloP100		-1.9
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: rs1554131; hg19: chr3-189604149;