rs1555710416

Variant names:

• chr18-55228950-GCCGA-AG
• rs1555710416
• NM_001083962.2:c.1772_1776delTCGGCinsCT

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM4_Supporting PP2 PP3 PP5_Moderate

The NM_001083962.2(TCF4):​c.1772_1776delTCGGCinsCT​(p.Leu591_Gly592delinsPro) variant causes a missense, disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TCF4 NM_001083962.2 missense, disruptive_inframe_deletion
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.32

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a domain bHLH (size 53) in uniprot entity ITF2_HUMAN there are 24 pathogenic changes around while only 0 benign (100%) in NM_001083962.2
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001083962.2. Strenght limited to Supporting due to length of the change: 1aa.
• PP2: Missense variant in the TCF4 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 42 curated pathogenic missense variants (we use a threshold of 10). The gene has 70 curated benign missense variants. Gene score misZ: 4.1035 (above the threshold of 3.09). Trascript score misZ: 4.5676 (above the threshold of 3.09). GenCC associations: The gene is linked to intellectual disability, corneal dystrophy, Fuchs endothelial, 3, autosomal dominant non-syndromic intellectual disability, autism spectrum disorder, Fuchs' endothelial dystrophy, Pitt-Hopkins syndrome.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 18-55228950-GCCGA-AG is Pathogenic according to our data. Variant chr18-55228950-GCCGA-AG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 520970.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCF4	NM_001083962.2	c.1772_1776delTCGGCinsCT	p.Leu591_Gly592delinsPro	missense_variant, disruptive_inframe_deletion		ENST00000354452.8	NP_001077431.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCF4	ENST00000354452.8	c.1772_1776delTCGGCinsCT	p.Leu591_Gly592delinsPro	missense_variant, disruptive_inframe_deletion		5	NM_001083962.2	ENSP00000346440.3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Mar 09, 2017

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Lines of evidence used in support of classification: LIKELY POSITIVE: Relevant Alteration(s) Detected -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555710416; hg19: chr18-52896181;