18-55222481-GA-G

Position:

• chr18-55222481-GA-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

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

• Frequency:
  • Genomes: 𝑓 0.0094 (24 hom., cov: 0)
  • Exomes 𝑓: 0.072 (0 hom.)
• Consequence: TCF4 NM_001083962.2 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U: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 -8 ACMG points.

• BA1: GnomAdExome4 highest population allele frequency = 0.0719 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCF4	NM_001083962.2	c.*5553del		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.*5553del		3_prime_UTR_variant	20/20	5	NM_001083962.2	ENSP00000346440	P3

Frequencies

GnomAD3 genomes AF: 0.00941 AC: 1346 AN: 143092 Hom.: 24 Cov.: 0

Gnomad AFR AF: 0.0283

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00640

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00525

Gnomad SAS AF: 0.0109

Gnomad FIN AF: 0.00138

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000962

Gnomad OTH AF: 0.00709

GnomAD4 exome AF: 0.0719 AC: 23 AN: 320 Hom.: 0 Cov.: 0 AF XY: 0.0865 AC XY: 18 AN XY: 208

Gnomad4 FIN exome AF: 0.0732

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00943 AC: 1350 AN: 143120 Hom.: 24 Cov.: 0 AF XY: 0.00996 AC XY: 690 AN XY: 69274

Gnomad4 AFR AF: 0.0283

Gnomad4 AMR AF: 0.00639

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00527

Gnomad4 SAS AF: 0.0110

Gnomad4 FIN AF: 0.00138

Gnomad4 NFE AF: 0.000962

Gnomad4 OTH AF: 0.00754

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Pitt-Hopkins syndrome Uncertain:1

Uncertain significance, 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;