chr12-50809588-C-T

Variant names:

• chr12-50809588-C-T
• rs1129406
• NM_005171.5:c.327C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_005171.5(ATF1):​c.327C>T​(p.Tyr109Tyr) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.389 in 1,608,190 control chromosomes in the GnomAD database, including 124,850 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (13308 hom., cov: 31)
  • Exomes 𝑓: 0.39 (111542 hom.)
• Consequence: ATF1 NM_005171.5 splice_region, synonymous
• Scores: Splicing: ADA: 0.004790
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.01

Genes affected

ATF1 (HGNC:783): (activating transcription factor 1) This gene encodes an activating transcription factor, which belongs to the ATF subfamily and bZIP (basic-region leucine zipper) family. It influences cellular physiologic processes by regulating the expression of downstream target genes, which are related to growth, survival, and other cellular activities. This protein is phosphorylated at serine 63 in its kinase-inducible domain by serine/threonine kinases, cAMP-dependent protein kinase A, calmodulin-dependent protein kinase I/II, mitogen- and stress-activated protein kinase and cyclin-dependent kinase 3 (cdk-3). Its phosphorylation enhances its transactivation and transcriptional activities, and enhances cell transformation. Fusion of this gene and FUS on chromosome 16 or EWSR1 on chromosome 22 induced by translocation generates chimeric proteins in angiomatoid fibrous histiocytoma and clear cell sarcoma. This gene has a pseudogene on chromosome 6. [provided by RefSeq, Aug 2010]

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 12-50809588-C-T is Benign according to our data. Variant chr12-50809588-C-T is described in ClinVar as [Benign]. Clinvar id is 1285794.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.01 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.532 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATF1	NM_005171.5	c.327C>T	p.Tyr109Tyr	splice_region_variant, synonymous_variant	Exon 4 of 7	ENST00000262053.8	NP_005162.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATF1	ENST00000262053.8	c.327C>T	p.Tyr109Tyr	splice_region_variant, synonymous_variant	Exon 4 of 7	1	NM_005171.5	ENSP00000262053.3

Frequencies

GnomAD3 genomes AF: 0.408 AC: 61769 AN: 151332 Hom.: 13289 Cov.: 31

Gnomad AFR AF: 0.538

Gnomad AMI AF: 0.273

Gnomad AMR AF: 0.294

Gnomad ASJ AF: 0.295

Gnomad EAS AF: 0.274

Gnomad SAS AF: 0.359

Gnomad FIN AF: 0.322

Gnomad MID AF: 0.357

Gnomad NFE AF: 0.390

Gnomad OTH AF: 0.410

GnomAD2 exomes AF: 0.353 AC: 88402 AN: 250102 AF XY: 0.356

Gnomad AFR exome AF: 0.543

Gnomad AMR exome AF: 0.226

Gnomad ASJ exome AF: 0.289

Gnomad EAS exome AF: 0.265

Gnomad FIN exome AF: 0.327

Gnomad NFE exome AF: 0.387

Gnomad OTH exome AF: 0.360

GnomAD4 exome AF: 0.387 AC: 563475 AN: 1456742 Hom.: 111542 Cov.: 37 AF XY: 0.386 AC XY: 279889 AN XY: 724926

Gnomad4 AFR exome AF: 0.535 AC: 17865 AN: 33380

Gnomad4 AMR exome AF: 0.235 AC: 10413 AN: 44244

Gnomad4 ASJ exome AF: 0.290 AC: 7571 AN: 26076

Gnomad4 EAS exome AF: 0.317 AC: 12585 AN: 39672

Gnomad4 SAS exome AF: 0.357 AC: 30669 AN: 85916

Gnomad4 FIN exome AF: 0.338 AC: 18023 AN: 53322

Gnomad4 NFE exome AF: 0.398 AC: 441202 AN: 1108210

Gnomad4 Remaining exome AF: 0.382 AC: 23014 AN: 60208

GnomAD4 genome AF: 0.408 AC: 61818 AN: 151448 Hom.: 13308 Cov.: 31 AF XY: 0.400 AC XY: 29613 AN XY: 73968

Gnomad4 AFR AF: 0.538 AC: 0.537655 AN: 0.537655

Gnomad4 AMR AF: 0.293 AC: 0.293457 AN: 0.293457

Gnomad4 ASJ AF: 0.295 AC: 0.294746 AN: 0.294746

Gnomad4 EAS AF: 0.273 AC: 0.272904 AN: 0.272904

Gnomad4 SAS AF: 0.359 AC: 0.359134 AN: 0.359134

Gnomad4 FIN AF: 0.322 AC: 0.322439 AN: 0.322439

Gnomad4 NFE AF: 0.390 AC: 0.389774 AN: 0.389774

Gnomad4 OTH AF: 0.408 AC: 0.40827 AN: 0.40827

Alfa AF: 0.389 Hom.: 42499

Bravo AF: 0.413

Asia WGS AF: 0.351 AC: 1221 AN: 3478

EpiCase AF: 0.386

EpiControl AF: 0.394

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 13, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 29547645, 26553438) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	14
DANN	Benign	0.76
Mutation Taster		=44/56	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0048
dbscSNV1_RF	Benign	0.084
SpliceAI score (max)		0.030		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: rs1129406; hg19: chr12-51203371; COSMIC: COSV50395907; COSMIC: COSV50395907;