18-55222481-G-GA

Position:

• chr18-55222481-G-GA

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001083962.2(TCF4):​c.*5553_*5554insT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.28 (5502 hom., cov: 0)
  • Exomes 𝑓: 0.30 (2 hom.)
• Consequence: TCF4 NM_001083962.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.662

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 -10 ACMG points.

• BP6: Variant 18-55222481-G-GA is Benign according to our data. Variant chr18-55222481-G-GA is described in ClinVar as [Benign]. Clinvar id is 327220.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.328 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCF4	NM_001083962.2	c.*5553_*5554insT		3_prime_UTR_variant	20/20	ENST00000354452.8	NP_001077431.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCF4	ENST00000354452.8	c.*5553_*5554insT		3_prime_UTR_variant	20/20	5	NM_001083962.2	ENSP00000346440	P3

Frequencies

GnomAD3 genomes AF: 0.282 AC: 40331 AN: 143026 Hom.: 5500 Cov.: 0

Gnomad AFR AF: 0.192

Gnomad AMI AF: 0.277

Gnomad AMR AF: 0.267

Gnomad ASJ AF: 0.319

Gnomad EAS AF: 0.310

Gnomad SAS AF: 0.206

Gnomad FIN AF: 0.336

Gnomad MID AF: 0.328

Gnomad NFE AF: 0.332

Gnomad OTH AF: 0.279

GnomAD4 exome AF: 0.301 AC: 101 AN: 336 Hom.: 2 Cov.: 0 AF XY: 0.294 AC XY: 63 AN XY: 214

Gnomad4 FIN exome AF: 0.298

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.282 AC: 40327 AN: 143060 Hom.: 5502 Cov.: 0 AF XY: 0.280 AC XY: 19387 AN XY: 69256

Gnomad4 AFR AF: 0.192

Gnomad4 AMR AF: 0.267

Gnomad4 ASJ AF: 0.319

Gnomad4 EAS AF: 0.309

Gnomad4 SAS AF: 0.206

Gnomad4 FIN AF: 0.336

Gnomad4 NFE AF: 0.332

Gnomad4 OTH AF: 0.276

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

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs71670792; hg19: chr18-52889712;