rs1800369

Variant names:

• chr17-7676532-G-A
• rs1800369
• NM_000546.6:c.63C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-7676532-G-A
• chr17-7676532-G-C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_000546.6(TP53):​c.63C>T​(p.Asp21Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00024 in 1,614,004 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene TP53 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00025 (4 hom.)
• Consequence: TP53 NM_000546.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:12
• Conservation: PhyloP100: 0.0590
• Publications: 18 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: ClinGen, G2P, Labcorp Genetics (formerly Invitae), 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

Specifications for TP53 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 17-7676532-G-A is Benign according to our data. Variant chr17-7676532-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 184112.
• BP7: Synonymous conserved (PhyloP=0.059 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000138 (21/152248) while in subpopulation SAS AF = 0.00435 (21/4830). AF 95% confidence interval is 0.00291. There are 0 homozygotes in GnomAd4. There are 13 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 21 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000546.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP53	NM_000546.6	MANE Select	c.63C>T	p.Asp21Asp	synonymous	Exon 2 of 11	NP_000537.3
	TP53	NM_001126112.3		c.63C>T	p.Asp21Asp	synonymous	Exon 2 of 11	NP_001119584.1	K7PPA8
	TP53	NM_001407262.1		c.63C>T	p.Asp21Asp	synonymous	Exon 3 of 12	NP_001394191.1	K7PPA8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP53	ENST00000269305.9	TSL:1 MANE Select	c.63C>T	p.Asp21Asp	synonymous	Exon 2 of 11	ENSP00000269305.4	P04637-1
	TP53	ENST00000445888.6	TSL:1	c.63C>T	p.Asp21Asp	synonymous	Exon 2 of 11	ENSP00000391478.2	P04637-1
	TP53	ENST00000455263.6	TSL:1	c.63C>T	p.Asp21Asp	synonymous	Exon 2 of 12	ENSP00000398846.2	P04637-3

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152130 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00434

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000535 AC: 134 AN: 250398 AF XY: 0.000685

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000250 AC: 366 AN: 1461756 Hom.: 4 Cov.: 35 AF XY: 0.000369 AC XY: 268 AN XY: 727172

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00403 AC: 348 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53304

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111998

Other (OTH) AF: 0.000232 AC: 14 AN: 60394

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152248 Hom.: 0 Cov.: 31 AF XY: 0.000175 AC XY: 13 AN XY: 74440

African (AFR) AF: 0.00 AC: 0 AN: 41542

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00435 AC: 21 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.0000792 Hom.: 0

Bravo AF: 0.0000151

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	3	not provided (3)
-	1	1	Li-Fraumeni syndrome (2)
-	-	2	not specified (2)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Familial cancer of breast (1)
-	-	1	Li-Fraumeni syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	8.4
DANN	Benign	0.83
PhyloP100		0.059
PromoterAI		0.0043	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: rs1800369; hg19: chr17-7579850;