rs41483647

chr18-55234376-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.1486+172T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 852,966 control chromosomes in the GnomAD database, including 5,325 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.11 (1022 hom., cov: 32)
  • Exomes 𝑓: 0.10 (4303 hom.)
• Consequence: TCF4 NM_001083962.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.401

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=-0.89).
• BP6: Variant 18-55234376-A-G is Benign according to our data. Variant chr18-55234376-A-G is described in ClinVar as [Benign]. Clinvar id is 672226.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.124 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCF4	NM_001083962.2	c.1486+172T>C		intron_variant		ENST00000354452.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCF4	ENST00000354452.8	c.1486+172T>C		intron_variant		5	NM_001083962.2	P3

Frequencies

GnomAD3 genomes AF: 0.108 AC: 16459 AN: 152050 Hom.: 1022 Cov.: 32

Gnomad AFR AF: 0.127

Gnomad AMI AF: 0.281

Gnomad AMR AF: 0.0917

Gnomad ASJ AF: 0.181

Gnomad EAS AF: 0.00366

Gnomad SAS AF: 0.116

Gnomad FIN AF: 0.0443

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.112

Gnomad OTH AF: 0.114

GnomAD4 exome AF: 0.104 AC: 73028 AN: 700798 Hom.: 4303 Cov.: 9 AF XY: 0.105 AC XY: 37642 AN XY: 357412

Gnomad4 AFR exome AF: 0.125

Gnomad4 AMR exome AF: 0.0694

Gnomad4 ASJ exome AF: 0.177

Gnomad4 EAS exome AF: 0.000960

Gnomad4 SAS exome AF: 0.120

Gnomad4 FIN exome AF: 0.0503

Gnomad4 NFE exome AF: 0.112

Gnomad4 OTH exome AF: 0.107

GnomAD4 genome AF: 0.108 AC: 16465 AN: 152168 Hom.: 1022 Cov.: 32 AF XY: 0.105 AC XY: 7838 AN XY: 74418

Gnomad4 AFR AF: 0.127

Gnomad4 AMR AF: 0.0915

Gnomad4 ASJ AF: 0.181

Gnomad4 EAS AF: 0.00367

Gnomad4 SAS AF: 0.115

Gnomad4 FIN AF: 0.0443

Gnomad4 NFE AF: 0.112

Gnomad4 OTH AF: 0.114

Alfa AF: 0.105 Hom.: 159

Bravo AF: 0.113

Asia WGS AF: 0.0630 AC: 221 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	3.6
Dann	Benign	0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs41483647; hg19: chr18-52901607;