22-42168601-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_001378418.1(TCF20):c.*44+8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000654 in 1,555,782 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0013 (2 hom., cov: 31)
  • Exomes 𝑓: 0.00059 (0 hom.)
• Consequence: TCF20 NM_001378418.1 splice_region, intron
• Scores: Splicing: ADA: 0.6455
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.21

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00128 (195/152304) while in subpopulation AMR AF= 0.0051 (78/15296). AF 95% confidence interval is 0.00419. There are 2 homozygotes in gnomad4. There are 116 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd at 196 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCF20	NM_001378418.1	c.*44+8G>A		splice_region_variant, intron_variant		ENST00000677622.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCF20	ENST00000677622.1	c.*44+8G>A		splice_region_variant, intron_variant			NM_001378418.1	P2

Frequencies

GnomAD3 genomes AF: 0.00129 AC: 196 AN: 152186 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.00157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00511

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.00383

GnomAD4 exome AF: 0.000586 AC: 822 AN: 1403478 Hom.: 0 Cov.: 31 AF XY: 0.000585 AC XY: 406 AN XY: 693854

Gnomad4 AFR exome AF: 0.000940

Gnomad4 AMR exome AF: 0.00277

Gnomad4 ASJ exome AF: 0.000197

Gnomad4 EAS exome AF: 0.0000274

Gnomad4 SAS exome AF: 0.0000124

Gnomad4 FIN exome AF: 0.0000228

Gnomad4 NFE exome AF: 0.000549

Gnomad4 OTH exome AF: 0.00117

GnomAD4 genome AF: 0.00128 AC: 195 AN: 152304 Hom.: 2 Cov.: 31 AF XY: 0.00156 AC XY: 116 AN XY: 74502

Gnomad4 AFR AF: 0.00154

Gnomad4 AMR AF: 0.00510

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000588

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.000971 Hom.: 0

Bravo AF: 0.00149

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental delay with variable intellectual impairment and behavioral abnormalities Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Apr 14, 2020

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
Cadd	Benign	13
Dann	Uncertain	0.98

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.65
dbscSNV1_RF	Benign	0.48
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs141457938; hg19: chr22-42564607;