22-42168712-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001378418.1(TCF20):c.5824C>G(p.Pro1942Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000387 in 1,611,374 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1942H) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00046 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00038 (2 hom.)
• Consequence: TCF20 NM_001378418.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.00

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.017077863).
• BP6: Variant 22-42168712-G-C is Benign according to our data. Variant chr22-42168712-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 2072362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00046 (70/152282) while in subpopulation AFR AF= 0.000963 (40/41548). AF 95% confidence interval is 0.000726. There are 0 homozygotes in gnomad4. There are 25 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 70 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCF20	NM_001378418.1	c.5824C>G	p.Pro1942Ala	missense_variant	5/6	ENST00000677622.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCF20	ENST00000677622.1	c.5824C>G	p.Pro1942Ala	missense_variant	5/6		NM_001378418.1	P2

Frequencies

GnomAD3 genomes AF: 0.000460 AC: 70 AN: 152164 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000445 AC: 109 AN: 244782 Hom.: 2 AF XY: 0.000445 AC XY: 59 AN XY: 132636

Gnomad AFR exome AF: 0.000953

Gnomad AMR exome AF: 0.000292

Gnomad ASJ exome AF: 0.000505

Gnomad EAS exome AF: 0.000274

Gnomad SAS exome AF: 0.000133

Gnomad FIN exome AF: 0.0000506

Gnomad NFE exome AF: 0.000614

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000380 AC: 554 AN: 1459092 Hom.: 2 Cov.: 31 AF XY: 0.000357 AC XY: 259 AN XY: 725698

Gnomad4 AFR exome AF: 0.000718

Gnomad4 AMR exome AF: 0.000359

Gnomad4 ASJ exome AF: 0.000499

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.000105

Gnomad4 FIN exome AF: 0.000191

Gnomad4 NFE exome AF: 0.000407

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.000460 AC: 70 AN: 152282 Hom.: 0 Cov.: 31 AF XY: 0.000336 AC XY: 25 AN XY: 74450

Gnomad4 AFR AF: 0.000963

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000451 Hom.: 1

Bravo AF: 0.000518

ExAC AF: 0.000453 AC: 55

EpiCase AF: 0.000600

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

TCF20-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 19, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 21, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	11
Dann	Benign	0.91
DEOGEN2	Benign	0.035	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.74	D
M_CAP	Benign	0.0083	T
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	D;D;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.33	N
REVEL	Benign	0.037
Sift	Uncertain	0.010	D
Sift4G	Benign	0.67	T
Polyphen		0.0	B
Vest4		0.33
MutPred		0.25		Loss of glycosylation at P1942 (P = 0.0121);
MVP		0.12
MPC		0.11
ClinPred		0.017	T
GERP RS		2.5
Varity_R		0.034
gMVP		0.28

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

Publications

LitVar

Other links and lift over

dbSNP: rs115095004; hg19: chr22-42564718;