chr18-55222736-T-C

Position:

• chr18-55222736-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001083962.2(TCF4):​c.*5299A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.433 in 152,464 control chromosomes in the GnomAD database, including 14,803 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (14772 hom., cov: 33)
  • Exomes 𝑓: 0.36 (31 hom.)
• Consequence: TCF4 NM_001083962.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0190

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 18-55222736-T-C is Benign according to our data. Variant chr18-55222736-T-C is described in ClinVar as [Benign]. Clinvar id is 327228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.556 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCF4	NM_001083962.2	c.*5299A>G		3_prime_UTR_variant	20/20	ENST00000354452.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCF4	ENST00000354452.8	c.*5299A>G		3_prime_UTR_variant	20/20	5	NM_001083962.2	P3

Frequencies

GnomAD3 genomes AF: 0.434 AC: 65905 AN: 151916 Hom.: 14762 Cov.: 33

Gnomad AFR AF: 0.563

Gnomad AMI AF: 0.543

Gnomad AMR AF: 0.387

Gnomad ASJ AF: 0.436

Gnomad EAS AF: 0.305

Gnomad SAS AF: 0.264

Gnomad FIN AF: 0.340

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.400

Gnomad OTH AF: 0.441

GnomAD4 exome AF: 0.361 AC: 156 AN: 432 Hom.: 31 Cov.: 0 AF XY: 0.369 AC XY: 96 AN XY: 260

Gnomad4 FIN exome AF: 0.357

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 1.00

GnomAD4 genome AF: 0.434 AC: 65937 AN: 152032 Hom.: 14772 Cov.: 33 AF XY: 0.425 AC XY: 31587 AN XY: 74304

Gnomad4 AFR AF: 0.562

Gnomad4 AMR AF: 0.387

Gnomad4 ASJ AF: 0.436

Gnomad4 EAS AF: 0.304

Gnomad4 SAS AF: 0.264

Gnomad4 FIN AF: 0.340

Gnomad4 NFE AF: 0.400

Gnomad4 OTH AF: 0.436

Alfa AF: 0.419 Hom.: 13996

Bravo AF: 0.447

Asia WGS AF: 0.303 AC: 1053 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 13, 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	-0.79
CADD	Benign	11
DANN	Benign	0.72

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1261085; hg19: chr18-52889967; COSMIC: COSV61900711; COSMIC: COSV61900711;