rs147445499

chr18-55261512-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 3P and 18B. PM1 PP2 BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001083962.2(TCF4):c.944C>T(p.Ala315Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00097 in 1,613,924 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Synonymous variant affecting the same amino acid position (i.e. A315A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00062 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (1 hom.)
• Consequence: TCF4 NM_001083962.2 missense
• Clinical Significance: Benign reviewed by expert panel B:11
• Conservation: PhyloP100: 7.26

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_001083962.2
• PP2: Missense variant where missense usually causes diseases, TCF4
• BP4: Computational evidence support a benign effect (MetaRNN=0.07375625).
• BP6: Variant 18-55261512-G-A is Benign according to our data. Variant chr18-55261512-G-A is described in ClinVar as [Benign]. Clinvar id is 160091.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr18-55261512-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000624 (95/152278) while in subpopulation NFE AF= 0.00103 (70/68020). AF 95% confidence interval is 0.000835. There are 0 homozygotes in gnomad4. There are 45 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 95 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCF4	NM_001083962.2	c.944C>T	p.Ala315Val	missense_variant	12/20	ENST00000354452.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCF4	ENST00000354452.8	c.944C>T	p.Ala315Val	missense_variant	12/20	5	NM_001083962.2	P3

Frequencies

GnomAD3 genomes AF: 0.000624 AC: 95 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000849

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000630 AC: 158 AN: 250760 Hom.: 0 AF XY: 0.000635 AC XY: 86 AN XY: 135488

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000554

Gnomad NFE exome AF: 0.00118

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.00101 AC: 1471 AN: 1461646 Hom.: 1 Cov.: 31 AF XY: 0.00104 AC XY: 755 AN XY: 727144

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000674

Gnomad4 NFE exome AF: 0.00126

Gnomad4 OTH exome AF: 0.000397

GnomAD4 genome AF: 0.000624 AC: 95 AN: 152278 Hom.: 0 Cov.: 32 AF XY: 0.000604 AC XY: 45 AN XY: 74462

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000849

Gnomad4 NFE AF: 0.00103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000687 Hom.: 0

Bravo AF: 0.000612

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000634 AC: 77

EpiCase AF: 0.000763

EpiControl AF: 0.000889

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 28, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 24, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Feb 16, 2015	- -

Pitt-Hopkins syndrome Benign:3

Benign, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Mar 26, 2021	The allele frequency of the p.Ala315Val variant in TCF4 is 0.1% in European (Non-Finnish) 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.Ala315Val variant is observed in at least 2 unaffected individuals (internal database) (BS2). The p.Ala315Val variant is found in a patient with an alternate molecular basis of disease (internal database) (BP5). In summary, the p.Ala315Val variant in TCF4 is classified as benign based on the ACMG/AMP criteria (BA1, BS2, BP5). -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 14, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	TCF4: PP2, BS1 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 05, 2017	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 06, 2018

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

TCF4-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 06, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.060
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;.;.;.;D;D;D;D;D;D;.;D;.;D;D;D;D;D;.;D;.;D;D;D;D;D;.;D;D;D;D;D;D;D;D
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.074	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.12	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.69	T
Sift4G	Uncertain	0.022	D;.;D;.;.;.;.;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;T;D;D;D;.;.;.
Polyphen		0.16, 0.63	.;.;B;.;.;.;.;.;.;B;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;P;.;.;.;.;.;.
Vest4		0.66
MVP		0.61
MPC		2.2
ClinPred		0.048	T
GERP RS		6.0
Varity_R		0.28
gMVP		0.46

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

Publications

LitVar

Other links and lift over

dbSNP: rs147445499; hg19: chr18-52928743;