18-55234615-C-G

Variant names:

• chr18-55234615-C-G
• rs143944746
• NM_001083962.2:c.1419G>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001083962.2(TCF4):​c.1419G>C​(p.Pro473Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00249 in 1,614,066 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P473P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0022 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (9 hom.)
• Consequence: TCF4 NM_001083962.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -4.43
• Publications: 3 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

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 18-55234615-C-G is Benign according to our data. Variant chr18-55234615-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93541.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.43 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00217 (330/152182) while in subpopulation NFE AF = 0.00273 (186/68008). AF 95% confidence interval is 0.00241. There are 3 homozygotes in GnomAd4. There are 153 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 330 AD gene.

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.1419G>C	p.Pro473Pro	synonymous	Exon 16 of 20	NP_001077431.1	P15884-3
	TCF4	NM_001243226.3		c.1725G>C	p.Pro575Pro	synonymous	Exon 17 of 21	NP_001230155.2	E9PH57
	TCF4	NM_001243228.2		c.1437G>C	p.Pro479Pro	synonymous	Exon 16 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.1419G>C	p.Pro473Pro	synonymous	Exon 16 of 20	ENSP00000346440.3	P15884-3
	TCF4	ENST00000398339.5	TSL:1	c.1725G>C	p.Pro575Pro	synonymous	Exon 17 of 21	ENSP00000381382.1	E9PH57
	TCF4	ENST00000356073.8	TSL:1	c.1419G>C	p.Pro473Pro	synonymous	Exon 16 of 20	ENSP00000348374.4	P15884-1

Frequencies

GnomAD3 genomes AF: 0.00217 AC: 330 AN: 152064 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.0228

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00273

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00226 AC: 567 AN: 251412 AF XY: 0.00216

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.00150

Gnomad ASJ exome AF: 0.0179

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00267

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00252 AC: 3688 AN: 1461884 Hom.: 9 Cov.: 31 AF XY: 0.00249 AC XY: 1813 AN XY: 727244

African (AFR) AF: 0.000568 AC: 19 AN: 33480

American (AMR) AF: 0.00132 AC: 59 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0180 AC: 471 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.000356 AC: 19 AN: 53420

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5768

European-Non Finnish (NFE) AF: 0.00264 AC: 2932 AN: 1112002

Other (OTH) AF: 0.00291 AC: 176 AN: 60396

GnomAD4 genome AF: 0.00217 AC: 330 AN: 152182 Hom.: 3 Cov.: 32 AF XY: 0.00206 AC XY: 153 AN XY: 74386

African (AFR) AF: 0.000554 AC: 23 AN: 41528

American (AMR) AF: 0.00177 AC: 27 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0228 AC: 79 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00273 AC: 186 AN: 68008

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00374 Hom.: 2

Bravo AF: 0.00238

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00333

EpiControl AF: 0.00308

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	2	Pitt-Hopkins syndrome (2)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.39
DANN	Benign	0.63
PhyloP100		-4.4
Mutation Taster		=100/0	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: rs143944746; hg19: chr18-52901846;