NM_001083962.2:c.759C>G

Variant names:

• chr18-55275649-G-C
• rs1555796785
• NM_001083962.2:c.759C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PP4 PM6_Strong PM2_Supporting PS4_Moderate

This summary comes from the ClinGen Evidence Repository: The p.Ser253Arg variant in TCF4 has been reported in at least 2 de novo occurrences (biological parentage unconfirmed) in individuals with Pitt–Hopkins syndrome (PMID 29322350; 26993267, described as p.Ser355Arg) (PM6_Strong). The p.Ser253Arg variant has been observed in 3 other individuals with Pitt-Hopkins syndrome (PMID 29322350; 26993267, described as p.Ser355Arg) (PS4_Moderate). The p.Ser253Arg variant in TCF4 is absent from gnomAD (PM2_Supporting). The p.Ser253Arg variant in TCF4 has been reported in an individual with a clinical phenotype suggestive of Pitt–Hopkins syndrome (PMID 26993267, described as p.Ser355Arg) (PP4). In summary, the p.Ser253Arg variant in TCF4 is classified as likely pathogenic for Pitt-Hopkins syndrome based on the ACMG/AMP criteria (PM6_strong, PS4_moderate, PM2_supporting, PP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA402701458/MONDO:0012589/016

• Frequency: Genomes: not found (cov: 32)
• Consequence: TCF4 NM_001083962.2 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 3.71
• Publications: 1 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

Specifications for TCF4 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

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.759C>G	p.Ser253Arg	missense	Exon 10 of 20	NP_001077431.1	P15884-3
	TCF4	NM_001243226.3		c.1065C>G	p.Ser355Arg	missense	Exon 11 of 21	NP_001230155.2	E9PH57
	TCF4	NM_001243228.2		c.777C>G	p.Ser259Arg	missense	Exon 10 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.759C>G	p.Ser253Arg	missense	Exon 10 of 20	ENSP00000346440.3	P15884-3
	TCF4	ENST00000398339.5	TSL:1	c.1065C>G	p.Ser355Arg	missense	Exon 11 of 21	ENSP00000381382.1	E9PH57
	TCF4	ENST00000356073.8	TSL:1	c.759C>G	p.Ser253Arg	missense	Exon 10 of 20	ENSP00000348374.4	P15884-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	Pitt-Hopkins syndrome (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Uncertain	0.017	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.081	T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		3.7
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.14
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.095	T
Polyphen		1.0	D
Vest4		0.82
MutPred		0.26		Loss of phosphorylation at S355 (P = 0.0545)
MVP		0.41
MPC		2.4
ClinPred		0.95	D
GERP RS		5.0
PromoterAI		-0.16	Neutral
Varity_R		0.47
gMVP		0.76
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.98		Position offset: 1
DS_DL_spliceai		0.76		Position offset: -30

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

Other links and lift over

dbSNP: rs1555796785; hg19: chr18-52942880;