18-55481790-A-T

Variant names:

• chr18-55481790-A-T
• rs2958182
• NM_001083962.2:c.146-17653T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001083962.2(TCF4):​c.146-17653T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.717 in 152,126 control chromosomes in the GnomAD database, including 39,740 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.72 (39740 hom., cov: 32)
• Consequence: TCF4 NM_001083962.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.969
• Publications: 18 publications found

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]

TCF4-AS1 (HGNC:51642): (TCF4 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.04).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.842 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001083962.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCF4	NM_001083962.2	MANE Select	c.146-17653T>A		intron	N/A	NP_001077431.1
	TCF4	NM_001243226.3		c.452-17653T>A		intron	N/A	NP_001230155.2
	TCF4	NM_001243228.2		c.146-17653T>A		intron	N/A	NP_001230157.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCF4	ENST00000354452.8	TSL:5 MANE Select	c.146-17653T>A		intron	N/A	ENSP00000346440.3
	TCF4	ENST00000398339.5	TSL:1	c.452-17653T>A		intron	N/A	ENSP00000381382.1
	TCF4	ENST00000356073.8	TSL:1	c.146-17653T>A		intron	N/A	ENSP00000348374.4

Frequencies

GnomAD3 genomes AF: 0.716 AC: 108912 AN: 152008 Hom.: 39694 Cov.: 32

Gnomad AFR AF: 0.849

Gnomad AMI AF: 0.592

Gnomad AMR AF: 0.630

Gnomad ASJ AF: 0.741

Gnomad EAS AF: 0.842

Gnomad SAS AF: 0.753

Gnomad FIN AF: 0.622

Gnomad MID AF: 0.753

Gnomad NFE AF: 0.658

Gnomad OTH AF: 0.730

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.717 AC: 109007 AN: 152126 Hom.: 39740 Cov.: 32 AF XY: 0.716 AC XY: 53265 AN XY: 74362

African (AFR) AF: 0.849 AC: 35256 AN: 41524

American (AMR) AF: 0.629 AC: 9621 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.741 AC: 2571 AN: 3470

East Asian (EAS) AF: 0.843 AC: 4343 AN: 5154

South Asian (SAS) AF: 0.753 AC: 3636 AN: 4826

European-Finnish (FIN) AF: 0.622 AC: 6568 AN: 10566

Middle Eastern (MID) AF: 0.759 AC: 223 AN: 294

European-Non Finnish (NFE) AF: 0.658 AC: 44722 AN: 67986

Other (OTH) AF: 0.724 AC: 1528 AN: 2110

Alfa AF: 0.678 Hom.: 4413

Bravo AF: 0.725

Asia WGS AF: 0.742 AC: 2582 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.23
DANN	Benign	0.40
PhyloP100		-0.97
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2958182; hg19: chr18-53149021;