18-55461078-C-T

Variant names:

• chr18-55461078-C-T
• rs773462232
• NM_001083962.2:c.245G>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 highest population minor allele frequency of the p.Ser82Asn variant in TCF4 in gnomAD v2.1.1 is 0.00006 in African/African American population (not sufficient to meet BS1 criteria). The p.Ser82Asn variant is observed in at least 2 unaffected individuals (internal database - GeneDx and Invitae) (BS2). Computational analysis prediction tools suggest that the p.Ser82Asn variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Ser82Asn variant in TCF4 is classified as likely benign based on the ACMG/AMP criteria (BS2, BP4). (TCF4 specifications v.3; approved on 8/30/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA8970611/MONDO:0012589/032

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 32)
• Consequence: TCF4 NM_001083962.2 missense
• Clinical Significance: Likely benign reviewed by expert panel U:1 B:2
• Conservation: PhyloP100: 1.05
• 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-AS1 (HGNC:51642): (TCF4 antisense RNA 1)

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCF4	NM_001083962.2	MANE Select	c.245G>A	p.Ser82Asn	missense	Exon 5 of 20	NP_001077431.1	P15884-3
	TCF4	NM_001243226.3		c.551G>A	p.Ser184Asn	missense	Exon 6 of 21	NP_001230155.2	E9PH57
	TCF4	NM_001243228.2		c.245G>A	p.Ser82Asn	missense	Exon 5 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.245G>A	p.Ser82Asn	missense	Exon 5 of 20	ENSP00000346440.3	P15884-3
	TCF4	ENST00000398339.5	TSL:1	c.551G>A	p.Ser184Asn	missense	Exon 6 of 21	ENSP00000381382.1	E9PH57
	TCF4	ENST00000356073.8	TSL:1	c.245G>A	p.Ser82Asn	missense	Exon 5 of 20	ENSP00000348374.4	P15884-1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152108 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250728 AF XY: 0.00

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152108 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74294

African (AFR) AF: 0.0000483 AC: 2 AN: 41408

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Likely benign

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	Benign	0.086
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	20
DANN	Benign	0.70
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.15
Eigen_PC	Benign	0.022
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L
PhyloP100		1.1
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	0.040	N
REVEL	Benign	0.055
Sift	Benign	0.12	T
Sift4G	Benign	0.39	T
Polyphen		0.0	B
Vest4		0.28
MutPred		0.12		Loss of phosphorylation at S184 (P = 0.0295)
MVP		0.30
MPC		0.55
ClinPred		0.18	T
GERP RS		4.2
Varity_R		0.080
gMVP		0.15
Mutation Taster		=86/14	polymorphism

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: rs773462232; hg19: chr18-53128309;