NM_001083962.2:c.991-142A>G

Variant names:

• chr18-55260169-T-C
• rs35969244
• NM_001083962.2:c.991-142A>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.991-142A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0952 in 684,884 control chromosomes in the GnomAD database, including 3,672 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (934 hom., cov: 32)
  • Exomes 𝑓: 0.093 (2738 hom.)
• Consequence: TCF4 NM_001083962.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.02
• Publications: 4 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=-0.91).
• BP6: Variant 18-55260169-T-C is Benign according to our data. Variant chr18-55260169-T-C is described in ClinVar as Benign. ClinVar VariationId is 672225.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.125 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCF4	NM_001083962.2	c.991-142A>G		intron_variant	Intron 12 of 19	ENST00000354452.8	NP_001077431.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCF4	ENST00000354452.8	c.991-142A>G		intron_variant	Intron 12 of 19	5	NM_001083962.2	ENSP00000346440.3

Frequencies

GnomAD3 genomes AF: 0.102 AC: 15498 AN: 152128 Hom.: 934 Cov.: 32

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.271

Gnomad AMR AF: 0.0833

Gnomad ASJ AF: 0.186

Gnomad EAS AF: 0.00365

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.0408

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0996

Gnomad OTH AF: 0.105

GnomAD4 exome AF: 0.0933 AC: 49689 AN: 532638 Hom.: 2738 AF XY: 0.0959 AC XY: 27637 AN XY: 288246

African (AFR) AF: 0.128 AC: 1744 AN: 13674

American (AMR) AF: 0.0656 AC: 1685 AN: 25682

Ashkenazi Jewish (ASJ) AF: 0.177 AC: 3207 AN: 18144

East Asian (EAS) AF: 0.000767 AC: 25 AN: 32614

South Asian (SAS) AF: 0.118 AC: 6648 AN: 56414

European-Finnish (FIN) AF: 0.0453 AC: 1697 AN: 37478

Middle Eastern (MID) AF: 0.111 AC: 246 AN: 2212

European-Non Finnish (NFE) AF: 0.0997 AC: 31629 AN: 317294

Other (OTH) AF: 0.0964 AC: 2808 AN: 29126

GnomAD4 genome AF: 0.102 AC: 15506 AN: 152246 Hom.: 934 Cov.: 32 AF XY: 0.0989 AC XY: 7361 AN XY: 74446

African (AFR) AF: 0.128 AC: 5328 AN: 41532

American (AMR) AF: 0.0831 AC: 1270 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.186 AC: 645 AN: 3472

East Asian (EAS) AF: 0.00366 AC: 19 AN: 5190

South Asian (SAS) AF: 0.111 AC: 537 AN: 4832

European-Finnish (FIN) AF: 0.0408 AC: 433 AN: 10608

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.0996 AC: 6777 AN: 68012

Other (OTH) AF: 0.104 AC: 220 AN: 2112

Alfa AF: 0.100 Hom.: 380

Bravo AF: 0.106

Asia WGS AF: 0.0600 AC: 212 AN: 3476

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	-0.91
CADD	Benign	0.27
DANN	Benign	0.23
PhyloP100		-1.0
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: rs35969244; hg19: chr18-52927400;