18-55228336-C-T

Variant names:

• chr18-55228336-C-T
• rs151150677
• NM_001083962.2:c.1905G>A

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.1905G>A​(p.Ala635Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000491 in 1,614,134 control chromosomes in the GnomAD database, including 11 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. A635A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0026 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (4 hom.)
• Consequence: TCF4 NM_001083962.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.03
• Publications: 1 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=-0.68).
• BP6: Variant 18-55228336-C-T is Benign according to our data. Variant chr18-55228336-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 139411.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.03 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00265 (403/152306) while in subpopulation AFR AF = 0.00938 (390/41572). AF 95% confidence interval is 0.00861. There are 7 homozygotes in GnomAd4. There are 185 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 403 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.1905G>A	p.Ala635Ala	synonymous	Exon 19 of 20	NP_001077431.1	P15884-3
	TCF4	NM_001243226.3		c.2211G>A	p.Ala737Ala	synonymous	Exon 20 of 21	NP_001230155.2	E9PH57
	TCF4	NM_001243228.2		c.1923G>A	p.Ala641Ala	synonymous	Exon 19 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.1905G>A	p.Ala635Ala	synonymous	Exon 19 of 20	ENSP00000346440.3	P15884-3
	TCF4	ENST00000398339.5	TSL:1	c.2211G>A	p.Ala737Ala	synonymous	Exon 20 of 21	ENSP00000381382.1	E9PH57
	TCF4	ENST00000356073.8	TSL:1	c.1893G>A	p.Ala631Ala	synonymous	Exon 19 of 20	ENSP00000348374.4	P15884-1

Frequencies

GnomAD3 genomes AF: 0.00264 AC: 402 AN: 152188 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00938

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000752 AC: 189 AN: 251336 AF XY: 0.000530

Gnomad AFR exome AF: 0.0110

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000266 AC: 389 AN: 1461828 Hom.: 4 Cov.: 34 AF XY: 0.000237 AC XY: 172 AN XY: 727222

African (AFR) AF: 0.00911 AC: 305 AN: 33480

American (AMR) AF: 0.000224 AC: 10 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000387 AC: 43 AN: 1111998

Other (OTH) AF: 0.000480 AC: 29 AN: 60394

GnomAD4 genome AF: 0.00265 AC: 403 AN: 152306 Hom.: 7 Cov.: 32 AF XY: 0.00248 AC XY: 185 AN XY: 74472

African (AFR) AF: 0.00938 AC: 390 AN: 41572

American (AMR) AF: 0.000457 AC: 7 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

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

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00128 Hom.: 1

Bravo AF: 0.00306

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Pitt-Hopkins syndrome (2)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	2.9
DANN	Benign	0.85
PhyloP100		-1.0
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs151150677; hg19: chr18-52895567; COSMIC: COSV100610249;