NM_001083962.2:c.269A>G

Variant names:

• chr18-55461054-T-C
• rs143244149
• NM_001083962.2:c.269A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BS2 BA1 BP4

This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Asn90Ser variant in TCF4 is 1.5% in Ashkenazi Jewish sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.Asn90Ser variant is observed in at least 2 unaffected individuals (internal database) (BS2). Computational analysis prediction tools suggest that the p.Asn90Ser variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Asn90Ser variant in TCF4 is classified as benign based on the ACMG/AMP criteria (BA1, BS2, BP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA234991/MONDO:0012589/016

• Frequency:
  • Genomes: 𝑓 0.00064 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (4 hom.)
• Consequence: TCF4 NM_001083962.2 missense
• Clinical Significance: Benign reviewed by expert panel B:8
• Conservation: PhyloP100: 4.26
• Publications: 9 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: Benign. The variant received -13 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.
• BA1: 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.269A>G	p.Asn90Ser	missense	Exon 5 of 20	NP_001077431.1	P15884-3
	TCF4	NM_001243226.3		c.575A>G	p.Asn192Ser	missense	Exon 6 of 21	NP_001230155.2	E9PH57
	TCF4	NM_001243228.2		c.269A>G	p.Asn90Ser	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.269A>G	p.Asn90Ser	missense	Exon 5 of 20	ENSP00000346440.3	P15884-3
	TCF4	ENST00000398339.5	TSL:1	c.575A>G	p.Asn192Ser	missense	Exon 6 of 21	ENSP00000381382.1	E9PH57
	TCF4	ENST00000356073.8	TSL:1	c.269A>G	p.Asn90Ser	missense	Exon 5 of 20	ENSP00000348374.4	P15884-1

Frequencies

GnomAD3 genomes AF: 0.000637 AC: 97 AN: 152162 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.0150

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000798 AC: 200 AN: 250778 AF XY: 0.000627

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.0156

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000212

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.000394 AC: 575 AN: 1461102 Hom.: 4 Cov.: 30 AF XY: 0.000374 AC XY: 272 AN XY: 726830

African (AFR) AF: 0.000448 AC: 15 AN: 33452

American (AMR) AF: 0.0000672 AC: 3 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 400 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39652

South Asian (SAS) AF: 0.00 AC: 0 AN: 86230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53364

Middle Eastern (MID) AF: 0.000868 AC: 5 AN: 5762

European-Non Finnish (NFE) AF: 0.0000864 AC: 96 AN: 1111534

Other (OTH) AF: 0.000928 AC: 56 AN: 60348

GnomAD4 genome AF: 0.000637 AC: 97 AN: 152162 Hom.: 1 Cov.: 32 AF XY: 0.000673 AC XY: 50 AN XY: 74334

African (AFR) AF: 0.000796 AC: 33 AN: 41448

American (AMR) AF: 0.000131 AC: 2 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.0150 AC: 52 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68018

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.000944 Hom.: 2

Bravo AF: 0.000650

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.000651 AC: 79

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	3	Pitt-Hopkins syndrome (3)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	20
DANN	Benign	0.90
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.025
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.94	N
PhyloP100		4.3
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	0.23	N
REVEL	Benign	0.061
Sift	Benign	0.78	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.42
MVP		0.33
MPC		0.47
ClinPred		0.027	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.037
gMVP		0.15
Mutation Taster		=77/23	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: rs143244149; hg19: chr18-53128285;