18-55222481-GAA-GAAA

Variant names:

• chr18-55222481-G-GA
• rs71670792
• NM_001083962.2:c.*5553dupT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001083962.2(TCF4):​c.*5553dupT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.28 (5502 hom., cov: 0)
  • Exomes 𝑓: 0.30 (2 hom.)
• Consequence: TCF4 NM_001083962.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.662
• 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 Gene-Disease associations (from GenCC):

• Pitt-Hopkins syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P, Ambry Genetics, 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 -10 ACMG points.

• BP6: Variant 18-55222481-G-GA is Benign according to our data. Variant chr18-55222481-G-GA is described in ClinVar as Benign. ClinVar VariationId is 327220.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.328 is higher than 0.05.

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.*5553dupT		3_prime_UTR	Exon 20 of 20	NP_001077431.1	P15884-3
	TCF4	NM_001243226.3		c.*5553dupT		3_prime_UTR	Exon 21 of 21	NP_001230155.2	E9PH57
	TCF4	NM_001243228.2		c.*5553dupT		3_prime_UTR	Exon 20 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.*5553dupT		3_prime_UTR	Exon 20 of 20	ENSP00000346440.3	P15884-3
	TCF4	ENST00000356073.8	TSL:1	c.*5553dupT		3_prime_UTR	Exon 20 of 20	ENSP00000348374.4	P15884-1
	TCF4	ENST00000638154.3	TSL:5	c.*5553dupT		3_prime_UTR	Exon 19 of 19	ENSP00000490625.2	A0A1B0GVR6

Frequencies

GnomAD3 genomes AF: 0.282 AC: 40331 AN: 143026 Hom.: 5500 Cov.: 0

Gnomad AFR AF: 0.192

Gnomad AMI AF: 0.277

Gnomad AMR AF: 0.267

Gnomad ASJ AF: 0.319

Gnomad EAS AF: 0.310

Gnomad SAS AF: 0.206

Gnomad FIN AF: 0.336

Gnomad MID AF: 0.328

Gnomad NFE AF: 0.332

Gnomad OTH AF: 0.279

GnomAD4 exome AF: 0.301 AC: 101 AN: 336 Hom.: 2 Cov.: 0 AF XY: 0.294 AC XY: 63 AN XY: 214

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.298 AC: 99 AN: 332

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AF: 0.500 AC: 2 AN: 4

GnomAD4 genome AF: 0.282 AC: 40327 AN: 143060 Hom.: 5502 Cov.: 0 AF XY: 0.280 AC XY: 19387 AN XY: 69256

African (AFR) AF: 0.192 AC: 7433 AN: 38620

American (AMR) AF: 0.267 AC: 3844 AN: 14396

Ashkenazi Jewish (ASJ) AF: 0.319 AC: 1068 AN: 3344

East Asian (EAS) AF: 0.309 AC: 1526 AN: 4934

South Asian (SAS) AF: 0.206 AC: 917 AN: 4462

European-Finnish (FIN) AF: 0.336 AC: 2929 AN: 8714

Middle Eastern (MID) AF: 0.324 AC: 90 AN: 278

European-Non Finnish (NFE) AF: 0.332 AC: 21725 AN: 65434

Other (OTH) AF: 0.276 AC: 549 AN: 1990

Alfa AF: 0.106 Hom.: 212

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Pitt-Hopkins syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.66
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs71670792; hg19: chr18-52889712; COSMIC: COSV61897916; COSMIC: COSV61897916;