rs1555923822

Variant names:

• chr22-42210236-C-CT
• rs1555923822
• NM_001378418.1:c.5069dupA

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.5069dupA​(p.Pro1692ThrfsTer28) 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. Q1690Q) has been classified as Uncertain significance. 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: 3.33
• 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: G2P, Illumina, ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• 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 22-42210236-C-CT is Pathogenic according to our data. Variant chr22-42210236-C-CT is described in ClinVar as Pathogenic. ClinVar VariationId is 520742.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378418.1. 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
	TCF20	NM_001378418.1	MANE Select	c.5069dupA	p.Pro1692ThrfsTer28	frameshift	Exon 2 of 6	NP_001365347.1	W5ZR30
	TCF20	NM_005650.4		c.5069dupA	p.Pro1692ThrfsTer28	frameshift	Exon 2 of 6	NP_005641.1	W5ZR30
	TCF20	NM_181492.3		c.5069dupA	p.Pro1692ThrfsTer28	frameshift	Exon 2 of 5	NP_852469.1	Q9UGU0-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCF20	ENST00000677622.1	MANE Select	c.5069dupA	p.Pro1692ThrfsTer28	frameshift	Exon 2 of 6	ENSP00000503828.1	Q9UGU0-1
	TCF20	ENST00000359486.8	TSL:1	c.5069dupA	p.Pro1692ThrfsTer28	frameshift	Exon 2 of 6	ENSP00000352463.3	Q9UGU0-1
	TCF20	ENST00000335626.8	TSL:1	c.5069dupA	p.Pro1692ThrfsTer28	frameshift	Exon 1 of 4	ENSP00000335561.4	Q9UGU0-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.3
Mutation Taster		=0/200	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1555923822;

hg19: chr22-42606242;