rs41483647

Variant names:

• chr18-55234376-A-G
• rs41483647
• NM_001083962.2:c.1486+172T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.401
• Publications: 3 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 Gene-Disease associations (from GenCC):

• Pitt-Hopkins syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P, ClinGen
• corneal dystrophy, Fuchs endothelial, 3

  Inheritance: AD Classification: STRONG Submitted by: G2P
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fuchs' endothelial dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autism spectrum disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• intellectual disability

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 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 VariationId is 672226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.124 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCF4	NM_001083962.2	c.1486+172T>C		intron_variant	Intron 16 of 19	ENST00000354452.8	NP_001077431.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCF4	ENST00000354452.8	c.1486+172T>C		intron_variant	Intron 16 of 19	5	NM_001083962.2	ENSP00000346440.3

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

African (AFR) AF: 0.125 AC: 2222 AN: 17730

American (AMR) AF: 0.0694 AC: 1743 AN: 25122

Ashkenazi Jewish (ASJ) AF: 0.177 AC: 2894 AN: 16338

East Asian (EAS) AF: 0.000960 AC: 31 AN: 32280

South Asian (SAS) AF: 0.120 AC: 6435 AN: 53446

European-Finnish (FIN) AF: 0.0503 AC: 1783 AN: 35448

Middle Eastern (MID) AF: 0.112 AC: 449 AN: 4012

European-Non Finnish (NFE) AF: 0.112 AC: 53767 AN: 481964

Other (OTH) AF: 0.107 AC: 3704 AN: 34458

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

African (AFR) AF: 0.127 AC: 5274 AN: 41490

American (AMR) AF: 0.0915 AC: 1399 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.181 AC: 629 AN: 3470

East Asian (EAS) AF: 0.00367 AC: 19 AN: 5180

South Asian (SAS) AF: 0.115 AC: 554 AN: 4824

European-Finnish (FIN) AF: 0.0443 AC: 470 AN: 10614

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.112 AC: 7596 AN: 67988

Other (OTH) AF: 0.114 AC: 240 AN: 2110

Alfa AF: 0.106 Hom.: 165

Bravo AF: 0.113

Asia WGS AF: 0.0630 AC: 221 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		0.40
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: rs41483647; hg19: chr18-52901607;