rs374907737

chr17-7674327-G-Achr17-7674327-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000546.6(TP53):c.673-37C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000166 in 1,326,402 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: TP53 NM_000546.6 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 0.389

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 17-7674327-G-A is Benign according to our data. Variant chr17-7674327-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 371964.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=1, Benign=1}.
• BS2: High AC in GnomAd at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6	c.673-37C>T		intron_variant		ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9	c.673-37C>T		intron_variant		1	NM_000546.6	P1

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 151684 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000727

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000236 AC: 59 AN: 250068 Hom.: 0 AF XY: 0.000325 AC XY: 44 AN XY: 135202

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00108

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000174 AC: 204 AN: 1174616 Hom.: 0 Cov.: 17 AF XY: 0.000216 AC XY: 129 AN XY: 597790

Gnomad4 AFR exome AF: 0.0000718

Gnomad4 AMR exome AF: 0.000180

Gnomad4 ASJ exome AF: 0.0000410

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00102

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000123

Gnomad4 OTH exome AF: 0.0000983

GnomAD4 genome AF: 0.000105 AC: 16 AN: 151786 Hom.: 0 Cov.: 30 AF XY: 0.000108 AC XY: 8 AN XY: 74150

Gnomad4 AFR AF: 0.0000725

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000139 Hom.: 0

Bravo AF: 0.0000907

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 17, 2015	The c.673-37C>T intronic alteration consists of a C to T substitution 37 nucleotides before coding exon 6 in the TP53 gene. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Li-Fraumeni syndrome 1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Sep 13, 2016	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 28, 2021

- -

TP53-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 31, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	6.1
Dann	Benign	0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs374907737; hg19: chr17-7577645;