22-42168711-G-T

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.5825C>A(p.Pro1942His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000335 in 1,611,216 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1942A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00035 (0 hom.)
• Consequence: TCF20 NM_001378418.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.29

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=0.007108003).
• BP6: Variant 22-42168711-G-T is Benign according to our data. Variant chr22-42168711-G-T is described in ClinVar as [Benign]. Clinvar id is 725819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00023 (35/152142) while in subpopulation AMR AF= 0.000982 (15/15282). AF 95% confidence interval is 0.000604. There are 0 homozygotes in gnomad4. There are 13 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 35 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCF20	NM_001378418.1	c.5825C>A	p.Pro1942His	missense_variant	5/6	ENST00000677622.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCF20	ENST00000677622.1	c.5825C>A	p.Pro1942His	missense_variant	5/6		NM_001378418.1	P2

Frequencies

GnomAD3 genomes AF: 0.000230 AC: 35 AN: 152142 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000953 AC: 232 AN: 243466 Hom.: 0 AF XY: 0.000705 AC XY: 93 AN XY: 131946

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00589

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000200

Gnomad FIN exome AF: 0.0000512

Gnomad NFE exome AF: 0.000181

Gnomad OTH exome AF: 0.000668

GnomAD4 exome AF: 0.000345 AC: 504 AN: 1459074 Hom.: 0 Cov.: 31 AF XY: 0.000306 AC XY: 222 AN XY: 725656

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00463

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000221

Gnomad4 FIN exome AF: 0.0000573

Gnomad4 NFE exome AF: 0.000234

Gnomad4 OTH exome AF: 0.000249

GnomAD4 genome AF: 0.000230 AC: 35 AN: 152142 Hom.: 0 Cov.: 31 AF XY: 0.000175 AC XY: 13 AN XY: 74324

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.000982

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000220

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000226 Hom.: 0

Bravo AF: 0.000514

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000840 AC: 102

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

TCF20-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 28, 2019

This variant is classified as 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

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.039	T
Eigen	Benign	-0.15
Eigen_PC	Benign	0.044
FATHMM_MKL	Uncertain	0.84	D
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.0071	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	0.72	D;D;D
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.31	N
REVEL	Benign	0.050
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.090	T
Polyphen		0.19	B
Vest4		0.33
MVP		0.10
MPC		0.13
ClinPred		0.054	T
GERP RS		4.8
Varity_R		0.12
gMVP		0.31

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: rs144341537; hg19: chr22-42564717; COSMIC: COSV59496883;