NM_001083962.2:c.337G>C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G113W) has been classified as Uncertain significance.

• 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
• 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: G2P, PanelApp Australia, Orphanet, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 VariationId is 468958.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001083962.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCF4	NM_001083962.2	MANE Select	c.337G>C	p.Gly113Arg	missense	Exon 6 of 20	NP_001077431.1	P15884-3
	TCF4	NM_001243226.3		c.643G>C	p.Gly215Arg	missense	Exon 7 of 21	NP_001230155.2	E9PH57
	TCF4	NM_001243228.2		c.337G>C	p.Gly113Arg	missense	Exon 6 of 20	NP_001230157.1	H3BTP3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCF4	ENST00000354452.8	TSL:5 MANE Select	c.337G>C	p.Gly113Arg	missense	Exon 6 of 20	ENSP00000346440.3	P15884-3
	TCF4	ENST00000398339.5	TSL:1	c.643G>C	p.Gly215Arg	missense	Exon 7 of 21	ENSP00000381382.1	E9PH57
	TCF4	ENST00000356073.8	TSL:1	c.337G>C	p.Gly113Arg	missense	Exon 6 of 20	ENSP00000348374.4	P15884-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Esophageal atresia;C0034194:Pyloric stenosis (1)
-	-	1	Pitt-Hopkins syndrome (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.20	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Uncertain	0.36	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		5.5
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.099	T
Polyphen		0.98	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
PromoterAI		0.040	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.44
gMVP		0.48
Mutation Taster		=51/49	polymorphism

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

Other links and lift over

dbSNP: rs1556050492; hg19: chr18-53070717;