rs35558939

chr3-189889530-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003722.5(TP63):c.1652+46G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0404 in 1,613,628 control chromosomes in the GnomAD database, including 1,442 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (89 hom., cov: 33)
  • Exomes 𝑓: 0.041 (1353 hom.)
• Consequence: TP63 NM_003722.5 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0130

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 3-189889530-G-A is Benign according to our data. Variant chr3-189889530-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 259130.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-189889530-G-A is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.06 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP63	NM_001114980.2	c.1370+46G>A		intron_variant		ENST00000354600.10
TP63	NM_003722.5	c.1652+46G>A		intron_variant		ENST00000264731.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP63	ENST00000264731.8	c.1652+46G>A		intron_variant		1	NM_003722.5	P4
TP63	ENST00000354600.10	c.1370+46G>A		intron_variant		1	NM_001114980.2	A1

Frequencies

GnomAD3 genomes AF: 0.0308 AC: 4686 AN: 152216 Hom.: 88 Cov.: 33

Gnomad AFR AF: 0.00967

Gnomad AMI AF: 0.0757

Gnomad AMR AF: 0.0304

Gnomad ASJ AF: 0.0490

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0159

Gnomad FIN AF: 0.0213

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.0460

Gnomad OTH AF: 0.0487

GnomAD3 exomes AF: 0.0324 AC: 8086 AN: 249466 Hom.: 176 AF XY: 0.0335 AC XY: 4513 AN XY: 134844

Gnomad AFR exome AF: 0.00794

Gnomad AMR exome AF: 0.0226

Gnomad ASJ exome AF: 0.0535

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0172

Gnomad FIN exome AF: 0.0252

Gnomad NFE exome AF: 0.0476

Gnomad OTH exome AF: 0.0389

GnomAD4 exome AF: 0.0414 AC: 60459 AN: 1461294 Hom.: 1353 Cov.: 32 AF XY: 0.0409 AC XY: 29750 AN XY: 726990

Gnomad4 AFR exome AF: 0.00995

Gnomad4 AMR exome AF: 0.0236

Gnomad4 ASJ exome AF: 0.0524

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.0185

Gnomad4 FIN exome AF: 0.0261

Gnomad4 NFE exome AF: 0.0467

Gnomad4 OTH exome AF: 0.0410

GnomAD4 genome AF: 0.0308 AC: 4686 AN: 152334 Hom.: 89 Cov.: 33 AF XY: 0.0301 AC XY: 2242 AN XY: 74490

Gnomad4 AFR AF: 0.00969

Gnomad4 AMR AF: 0.0303

Gnomad4 ASJ AF: 0.0490

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.0161

Gnomad4 FIN AF: 0.0213

Gnomad4 NFE AF: 0.0461

Gnomad4 OTH AF: 0.0477

Alfa AF: 0.0426 Hom.: 43

Bravo AF: 0.0313

Asia WGS AF: 0.0140 AC: 50 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 17, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
Cadd	Benign	10
Dann	Benign	0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs35558939; hg19: chr3-189607319; COSMIC: COSV53203242;