rs1555924435

Variant names:

• chr22-42210937-CG-C
• rs1555924435
• NM_001378418.1:c.4368delC

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001378418.1(TCF20):​c.4368delC​(p.Gly1457GlufsTer8) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. A1456A) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TCF20 NM_001378418.1 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.0500
• Publications: 0 publications found

Genes affected

TCF20 (HGNC:11631): (transcription factor 20) This gene encodes a transcription factor that recognizes the platelet-derived growth factor-responsive element in the matrix metalloproteinase 3 promoter. The encoded protein is thought to be a transcriptional coactivator, enhancing the activity of transcription factors such as JUN and SP1. Mutations in this gene are associated with autism spectrum disorders. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2015]

TCF20 Gene-Disease associations (from GenCC):

• developmental delay with variable intellectual impairment and behavioral abnormalities

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Illumina
• syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 22-42210937-CG-C is Pathogenic according to our data. Variant chr22-42210937-CG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 521280.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCF20	NM_001378418.1	c.4368delC	p.Gly1457GlufsTer8	frameshift_variant	Exon 2 of 6	ENST00000677622.1	NP_001365347.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCF20	ENST00000677622.1	c.4368delC	p.Gly1457GlufsTer8	frameshift_variant	Exon 2 of 6		NM_001378418.1	ENSP00000503828.1
TCF20	ENST00000359486.8	c.4368delC	p.Gly1457GlufsTer8	frameshift_variant	Exon 2 of 6	1		ENSP00000352463.3
TCF20	ENST00000335626.8	c.4368delC	p.Gly1457GlufsTer8	frameshift_variant	Exon 1 of 4	1		ENSP00000335561.4
TCF20	ENST00000683686.1	c.4368delC	p.Gly1457GlufsTer8	frameshift_variant	Exon 2 of 6			ENSP00000508272.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Nov 02, 2016

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.050
Mutation Taster		=4/196	disease causing (ClinVar)

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: rs1555924435; hg19: chr22-42606943;