18-55222929-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001083962.2(TCF4):c.*5106T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.49 in 152,490 control chromosomes in the GnomAD database, including 19,303 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.49 (19272 hom., cov: 33)
  • Exomes 𝑓: 0.37 (31 hom.)
• Consequence: TCF4 NM_001083962.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.355

Genes affected

TCF4 (HGNC:11634): (transcription factor 4) This gene encodes transcription factor 4, a basic helix-loop-helix transcription factor. The encoded protein recognizes an Ephrussi-box ('E-box') binding site ('CANNTG') - a motif first identified in immunoglobulin enhancers. This gene is broadly expressed, and may play an important role in nervous system development. Defects in this gene are a cause of Pitt-Hopkins syndrome. In addition, an intronic CTG repeat normally numbering 10-37 repeat units can expand to >50 repeat units and cause Fuchs endothelial corneal dystrophy. Multiple alternatively spliced transcript variants that encode different proteins have been described. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 18-55222929-A-G is Benign according to our data. Variant chr18-55222929-A-G is described in ClinVar as [Benign]. Clinvar id is 327231.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.661 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCF4	NM_001083962.2	c.*5106T>C		3_prime_UTR_variant	20/20	ENST00000354452.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCF4	ENST00000354452.8	c.*5106T>C		3_prime_UTR_variant	20/20	5	NM_001083962.2	P3

Frequencies

GnomAD3 genomes AF: 0.490 AC: 74430 AN: 151948 Hom.: 19239 Cov.: 33

Gnomad AFR AF: 0.667

Gnomad AMI AF: 0.564

Gnomad AMR AF: 0.418

Gnomad ASJ AF: 0.481

Gnomad EAS AF: 0.305

Gnomad SAS AF: 0.281

Gnomad FIN AF: 0.353

Gnomad MID AF: 0.532

Gnomad NFE AF: 0.447

Gnomad OTH AF: 0.494

GnomAD4 exome AF: 0.374 AC: 158 AN: 422 Hom.: 31 Cov.: 0 AF XY: 0.377 AC XY: 95 AN XY: 252

Gnomad4 FIN exome AF: 0.370

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 1.00

GnomAD4 genome AF: 0.490 AC: 74505 AN: 152068 Hom.: 19272 Cov.: 33 AF XY: 0.479 AC XY: 35640 AN XY: 74328

Gnomad4 AFR AF: 0.668

Gnomad4 AMR AF: 0.418

Gnomad4 ASJ AF: 0.481

Gnomad4 EAS AF: 0.304

Gnomad4 SAS AF: 0.281

Gnomad4 FIN AF: 0.353

Gnomad4 NFE AF: 0.447

Gnomad4 OTH AF: 0.489

Alfa AF: 0.425 Hom.: 6113

Bravo AF: 0.508

Asia WGS AF: 0.323 AC: 1124 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Pitt-Hopkins syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	1.2
Dann	Benign	0.49

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1261084; hg19: chr18-52890160; COSMIC: COSV61908583; COSMIC: COSV61908583;