rs35850753

Variant names:

• chr17-7675353-C-T
• rs35850753
• ENST00000504937.5:c.-138G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000504937.5(TP53):​c.-138G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0171 in 1,531,386 control chromosomes in the GnomAD database, including 264 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (25 hom., cov: 31)
  • Exomes 𝑓: 0.018 (239 hom.)
• Consequence: TP53 ENST00000504937.5 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.39
• Publications: 31 publications found

Genes affected

TP53 (HGNC:11998): (tumor protein p53) This gene encodes a tumor suppressor protein containing transcriptional activation, DNA binding, and oligomerization domains. The encoded protein responds to diverse cellular stresses to regulate expression of target genes, thereby inducing cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism. Mutations in this gene are associated with a variety of human cancers, including hereditary cancers such as Li-Fraumeni syndrome. Alternative splicing of this gene and the use of alternate promoters result in multiple transcript variants and isoforms. Additional isoforms have also been shown to result from the use of alternate translation initiation codons from identical transcript variants (PMIDs: 12032546, 20937277). [provided by RefSeq, Dec 2016]

TP53 Gene-Disease associations (from GenCC):

• breast cancer

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• Li-Fraumeni syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet
• Li-Fraumeni syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp
• adrenocortical carcinoma, hereditary

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• sarcoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• bone marrow failure syndrome 5

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• colorectal cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• choroid plexus carcinoma

  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=-0.92).
• BP6: Variant 17-7675353-C-T is Benign according to our data. Variant chr17-7675353-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 670316.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0129 (1951/151066) while in subpopulation NFE AF = 0.0206 (1397/67894). AF 95% confidence interval is 0.0197. There are 25 homozygotes in GnomAd4. There are 942 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1951 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000504937.5. 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
	TP53	NM_000546.6	MANE Select	c.376-117G>A		intron	N/A	NP_000537.3
	TP53	NM_001126112.3		c.376-117G>A		intron	N/A	NP_001119584.1
	TP53	NM_001407262.1		c.376-117G>A		intron	N/A	NP_001394191.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP53	ENST00000504937.5	TSL:1	c.-138G>A		5_prime_UTR	Exon 1 of 7	ENSP00000481179.1
	TP53	ENST00000619186.4	TSL:1	c.-219G>A		5_prime_UTR	Exon 1 of 7	ENSP00000484375.1
	TP53	ENST00000504290.5	TSL:1	c.-138G>A		5_prime_UTR	Exon 1 of 8	ENSP00000484409.1

Frequencies

GnomAD3 genomes AF: 0.0129 AC: 1950 AN: 151004 Hom.: 25 Cov.: 31

Gnomad AFR AF: 0.00366

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00529

Gnomad ASJ AF: 0.00433

Gnomad EAS AF: 0.000391

Gnomad SAS AF: 0.00334

Gnomad FIN AF: 0.0267

Gnomad MID AF: 0.00325

Gnomad NFE AF: 0.0206

Gnomad OTH AF: 0.00674

GnomAD4 exome AF: 0.0176 AC: 24244 AN: 1380320 Hom.: 239 Cov.: 40 AF XY: 0.0174 AC XY: 11853 AN XY: 681334

African (AFR) AF: 0.00262 AC: 82 AN: 31320

American (AMR) AF: 0.00515 AC: 180 AN: 34972

Ashkenazi Jewish (ASJ) AF: 0.00591 AC: 146 AN: 24718

East Asian (EAS) AF: 0.00131 AC: 47 AN: 35742

South Asian (SAS) AF: 0.00405 AC: 317 AN: 78218

European-Finnish (FIN) AF: 0.0249 AC: 906 AN: 36410

Middle Eastern (MID) AF: 0.00283 AC: 12 AN: 4246

European-Non Finnish (NFE) AF: 0.0203 AC: 21873 AN: 1077096

Other (OTH) AF: 0.0118 AC: 681 AN: 57598

GnomAD4 genome AF: 0.0129 AC: 1951 AN: 151066 Hom.: 25 Cov.: 31 AF XY: 0.0128 AC XY: 942 AN XY: 73698

African (AFR) AF: 0.00367 AC: 151 AN: 41104

American (AMR) AF: 0.00528 AC: 80 AN: 15148

Ashkenazi Jewish (ASJ) AF: 0.00433 AC: 15 AN: 3468

East Asian (EAS) AF: 0.000392 AC: 2 AN: 5100

South Asian (SAS) AF: 0.00335 AC: 16 AN: 4772

European-Finnish (FIN) AF: 0.0267 AC: 275 AN: 10298

Middle Eastern (MID) AF: 0.00355 AC: 1 AN: 282

European-Non Finnish (NFE) AF: 0.0206 AC: 1397 AN: 67894

Other (OTH) AF: 0.00670 AC: 14 AN: 2088

Alfa AF: 0.0150 Hom.: 10

Bravo AF: 0.0108

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 15, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.25
DANN	Benign	0.57
PhyloP100		-3.4
PromoterAI		-0.018	Neutral
Mutation Taster		=100/0	polymorphism

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: rs35850753; hg19: chr17-7578671; COSMIC: COSV104370796;