NM_001083962.2:c.469C>G

Variant names:

• chr18-55350904-G-C
• rs587784464
• NM_001083962.2:c.469C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001083962.2(TCF4):​c.469C>G​(p.Arg157Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,276 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R157Q) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TCF4 NM_001083962.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.57
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCF4	NM_001083962.2	c.469C>G	p.Arg157Gly	missense_variant	Exon 7 of 20	ENST00000354452.8	NP_001077431.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCF4	ENST00000354452.8	c.469C>G	p.Arg157Gly	missense_variant	Exon 7 of 20	5	NM_001083962.2	ENSP00000346440.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461276 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726944

African (AFR) AF: 0.00 AC: 0 AN: 33428

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111564

Other (OTH) AF: 0.00 AC: 0 AN: 60360

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T;D;.;T;T;.;D;.;.;.;.;.;.;T;.;.;.;.;.;.;.;.;T;T;T;T;.;T;.;T;.;.;T;.;T;T;.;T;.;.;T;.;.;.;T;T;T;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Pathogenic	0.99	.;.;.;D;D;D;D;.;D;.;D;D;D;D;.;D;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.64	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.059	D
MutationAssessor	Uncertain	2.5	.;M;.;.;.;.;M;M;M;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
PhyloP100		5.6
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-4.2	.;D;.;.;.;.;D;D;.;D;D;D;D;D;D;D;D;D;.;D;D;D;.;.;.;D;.;.;D;D;.;.;D;.;D;.;D;D;.;.;.;.;.;D;.;.;D;.
REVEL	Uncertain	0.34
Sift	Uncertain	0.0050	.;D;.;.;.;.;D;D;.;D;D;D;D;D;D;D;D;D;.;D;D;D;.;.;.;D;.;.;D;D;.;.;D;.;D;.;D;D;.;.;.;.;.;D;.;.;D;.
Sift4G	Uncertain	0.0090	.;D;.;.;.;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;T;D;.;.;.;.;.;.;.;.;D;.;.;D;.;.;.;.;.;D;D;D;D;.;.;D;D;D
Polyphen		1.0	.;D;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.58, 0.59, 0.57, 0.57, 0.58, 0.57, 0.57, 0.36, 0.60, 0.60, 0.61, 0.55, 0.50, 0.62, 0.60
MutPred		0.21		.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;Loss of MoRF binding (P = 0.0425);.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.77
MPC		0.76
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.53
gMVP		0.79

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: rs587784464; hg19: chr18-53018135;