18-55403486-C-G

Variant names:

• chr18-55403486-C-G
• rs1556050492
• NM_001083962.2:c.337G>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP6_Moderate

The NM_001083962.2(TCF4):​c.337G>C​(p.Gly113Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TCF4 NM_001083962.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: 5.52

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the TCF4 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 42 curated pathogenic missense variants (we use a threshold of 10). The gene has 70 curated benign missense variants. Gene score misZ: 4.1035 (above the threshold of 3.09). Trascript score misZ: 4.5676 (above the threshold of 3.09). GenCC associations: The gene is linked to intellectual disability, corneal dystrophy, Fuchs endothelial, 3, autosomal dominant non-syndromic intellectual disability, autism spectrum disorder, Fuchs' endothelial dystrophy, Pitt-Hopkins syndrome.
• BP6: Variant 18-55403486-C-G is Benign according to our data. Variant chr18-55403486-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 468958.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCF4	NM_001083962.2	c.337G>C	p.Gly113Arg	missense_variant	Exon 6 of 20	ENST00000354452.8	NP_001077431.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCF4	ENST00000354452.8	c.337G>C	p.Gly113Arg	missense_variant	Exon 6 of 20	5	NM_001083962.2	ENSP00000346440.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Esophageal atresia;C0034194:Pyloric stenosis Uncertain:1

May 22, 2019

Clinical Genetics, Erasmus University Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Pitt-Hopkins syndrome Benign:1

May 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	.;D;.;T;.;D;.;.;.;.;.;.;T;.;.;.;.;.;.;.;.;.;T;.;T;.;.;T;.;.;T;T;T;.;.;T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	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	0.20	D
MetaRNN	Uncertain	0.62	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	0.36	D
MutationAssessor	Uncertain	2.3	.;M;.;.;.;M;M;M;.;.;.;.;.;.;.;M;.;M;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.7	.;D;.;.;.;D;D;.;D;D;D;D;D;D;D;D;.;D;.;D;D;.;.;.;D;.;.;.;.;D;.;D;D;.;D;D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0010	.;D;.;.;.;D;D;.;D;D;D;D;D;D;D;T;.;T;.;D;D;.;.;.;D;.;.;.;.;D;.;D;D;.;D;D
Sift4G	Benign	0.099	T;D;.;.;.;D;D;D;D;D;D;D;D;D;D;T;D;T;T;D;D;.;.;.;.;.;D;D;D;.;.;D;D;D;.;.
Polyphen		0.98, 1.0	.;D;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.75
MutPred		0.17		.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;Gain of MoRF binding (P = 0.0161);.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.90
MPC		1.6
ClinPred		0.99	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.44
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1556050492; hg19: chr18-53070717;