rs9957668

Variant names:

• chr18-55510439-T-C
• rs9957668
• NM_001083962.2:c.146-46302A>G

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.146-46302A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.344 in 505,256 control chromosomes in the GnomAD database, including 30,681 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (8996 hom., cov: 32)
  • Exomes 𝑓: 0.35 (21685 hom.)
• Consequence: TCF4 NM_001083962.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.88
• Publications: 9 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=-0.9).
• BP6: Variant 18-55510439-T-C is Benign according to our data. Variant chr18-55510439-T-C is described in ClinVar as Benign. ClinVar VariationId is 679855.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.482 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCF4	NM_001083962.2	c.146-46302A>G		intron_variant	Intron 3 of 19	ENST00000354452.8	NP_001077431.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCF4	ENST00000354452.8	c.146-46302A>G		intron_variant	Intron 3 of 19	5	NM_001083962.2	ENSP00000346440.3

Frequencies

GnomAD3 genomes AF: 0.340 AC: 51606 AN: 151908 Hom.: 8995 Cov.: 32

Gnomad AFR AF: 0.307

Gnomad AMI AF: 0.289

Gnomad AMR AF: 0.258

Gnomad ASJ AF: 0.405

Gnomad EAS AF: 0.498

Gnomad SAS AF: 0.351

Gnomad FIN AF: 0.370

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.359

Gnomad OTH AF: 0.331

GnomAD4 exome AF: 0.345 AC: 122008 AN: 353230 Hom.: 21685 AF XY: 0.343 AC XY: 61043 AN XY: 178116

African (AFR) AF: 0.293 AC: 2659 AN: 9066

American (AMR) AF: 0.217 AC: 1820 AN: 8368

Ashkenazi Jewish (ASJ) AF: 0.398 AC: 3878 AN: 9754

East Asian (EAS) AF: 0.436 AC: 10095 AN: 23144

South Asian (SAS) AF: 0.300 AC: 4283 AN: 14288

European-Finnish (FIN) AF: 0.333 AC: 6486 AN: 19450

Middle Eastern (MID) AF: 0.302 AC: 476 AN: 1574

European-Non Finnish (NFE) AF: 0.345 AC: 85607 AN: 247994

Other (OTH) AF: 0.342 AC: 6704 AN: 19592

GnomAD4 genome AF: 0.340 AC: 51613 AN: 152026 Hom.: 8996 Cov.: 32 AF XY: 0.337 AC XY: 25006 AN XY: 74296

African (AFR) AF: 0.306 AC: 12706 AN: 41468

American (AMR) AF: 0.258 AC: 3939 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.405 AC: 1405 AN: 3468

East Asian (EAS) AF: 0.498 AC: 2572 AN: 5168

South Asian (SAS) AF: 0.350 AC: 1686 AN: 4812

European-Finnish (FIN) AF: 0.370 AC: 3905 AN: 10558

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.359 AC: 24373 AN: 67956

Other (OTH) AF: 0.327 AC: 690 AN: 2110

Alfa AF: 0.351 Hom.: 36587

Bravo AF: 0.333

Asia WGS AF: 0.367 AC: 1281 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	-0.90
CADD	Benign	0.39
DANN	Benign	0.48
PhyloP100		-1.9
PromoterAI		0.056	Neutral
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: rs9957668; hg19: chr18-53177670; COSMIC: COSV61902129;