rs796053413

Variant names:

• chr18-55403518-C-T
• rs796053413
• NM_001083962.2:c.305G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

This summary comes from the ClinGen Evidence Repository: The p.Ser102Asn variant in TCF4 is present in 1 XX individual in gnomAD v4.0 (0.00016%) (not sufficient to meet BS1 criteria). The p.Ser102Asn variant is observed in at least 2 unaffected individuals (internal database - GeneDx) (BS2). Computational analysis prediction tools suggest that the p.Ser102Asn variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Ser102Asn variant in TCF4 is classified as likely benign based on the ACMG/AMP criteria (BS2, BP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA319094/MONDO:0012589/032

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TCF4 NM_001083962.2 missense, splice_region
• Scores: Splicing: ADA: 0.9978
• Clinical Significance: Likely benign reviewed by expert panel U:1 B:2
• Conservation: PhyloP100: 5.56
• Publications: 2 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: Likely_benign. The variant received -5 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCF4	NM_001083962.2	MANE Select	c.305G>A	p.Ser102Asn	missense splice_region	Exon 6 of 20	NP_001077431.1
	TCF4	NM_001243226.3		c.611G>A	p.Ser204Asn	missense splice_region	Exon 7 of 21	NP_001230155.2
	TCF4	NM_001243228.2		c.305G>A	p.Ser102Asn	missense splice_region	Exon 6 of 20	NP_001230157.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCF4	ENST00000354452.8	TSL:5 MANE Select	c.305G>A	p.Ser102Asn	missense splice_region	Exon 6 of 20	ENSP00000346440.3
	TCF4	ENST00000398339.5	TSL:1	c.611G>A	p.Ser204Asn	missense splice_region	Exon 7 of 21	ENSP00000381382.1
	TCF4	ENST00000356073.8	TSL:1	c.305G>A	p.Ser102Asn	missense splice_region	Exon 6 of 20	ENSP00000348374.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461578 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727098

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111790

Other (OTH) AF: 0.00 AC: 0 AN: 60376

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.095	T
BayesDel_noAF	Benign	-0.48
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.021	T
Eigen	Benign	0.038
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.0	T
PhyloP100		5.6
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.14
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.035	D
Vest4		0.39
MutPred		0.33		Gain of ubiquitination at K33 (P = 0.0339)
MVP		0.26
ClinPred		0.50	T
GERP RS		6.0
PromoterAI		0.018	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.14
Mutation Taster		=51/49	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.75
SpliceAI score (max)		0.040		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: rs796053413; hg19: chr18-53070749;