rs35850753

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1951 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6	c.376-117G>A		intron_variant	Intron 4 of 10	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.376-117G>A		intron_variant	Intron 4 of 10	1	NM_000546.6	ENSP00000269305.4

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

Gnomad4 AFR exome AF: 0.00262

Gnomad4 AMR exome AF: 0.00515

Gnomad4 ASJ exome AF: 0.00591

Gnomad4 EAS exome AF: 0.00131

Gnomad4 SAS exome AF: 0.00405

Gnomad4 FIN exome AF: 0.0249

Gnomad4 NFE exome AF: 0.0203

Gnomad4 OTH exome AF: 0.0118

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

Gnomad4 AFR AF: 0.00367

Gnomad4 AMR AF: 0.00528

Gnomad4 ASJ AF: 0.00433

Gnomad4 EAS AF: 0.000392

Gnomad4 SAS AF: 0.00335

Gnomad4 FIN AF: 0.0267

Gnomad4 NFE AF: 0.0206

Gnomad4 OTH AF: 0.00670

Alfa AF: 0.0211 Hom.: 6

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.25
DANN	Benign	0.57

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

Publications

LitVar

Other links and lift over

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