22-42168712-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.5824C>A(p.Pro1942Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000111 in 1,611,380 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Likely 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 0.00011 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00011 (1 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=0.014916211).
• BP6: Variant 22-42168712-G-T is Benign according to our data. Variant chr22-42168712-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 1711554.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000112 (17/152282) while in subpopulation SAS AF= 0.00104 (5/4828). AF 95% confidence interval is 0.000408. There are 0 homozygotes in gnomad4. There are 9 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCF20	NM_001378418.1	c.5824C>A	p.Pro1942Thr	missense_variant	5/6	ENST00000677622.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCF20	ENST00000677622.1	c.5824C>A	p.Pro1942Thr	missense_variant	5/6		NM_001378418.1	P2

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152164 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000237 AC: 58 AN: 244782 Hom.: 0 AF XY: 0.000302 AC XY: 40 AN XY: 132636

Gnomad AFR exome AF: 0.0000635

Gnomad AMR exome AF: 0.000175

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000110

Gnomad SAS exome AF: 0.00119

Gnomad FIN exome AF: 0.000152

Gnomad NFE exome AF: 0.0000722

Gnomad OTH exome AF: 0.000333

GnomAD4 exome AF: 0.000111 AC: 162 AN: 1459098 Hom.: 1 Cov.: 31 AF XY: 0.000131 AC XY: 95 AN XY: 725702

Gnomad4 AFR exome AF: 0.000150

Gnomad4 AMR exome AF: 0.000270

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000873

Gnomad4 FIN exome AF: 0.0000764

Gnomad4 NFE exome AF: 0.0000450

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152282 Hom.: 0 Cov.: 31 AF XY: 0.000121 AC XY: 9 AN XY: 74450

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000113 Hom.: 1

Bravo AF: 0.0000718

ExAC AF: 0.000288 AC: 35

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2022	TCF20: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	17
Dann	Uncertain	0.98
DEOGEN2	Benign	0.040	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.72	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.015	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	0.10	N
REVEL	Benign	0.041
Sift	Uncertain	0.012	D
Sift4G	Benign	0.84	T
Polyphen		0.0020	B
Vest4		0.45
MutPred		0.23		Loss of catalytic residue at P1941 (P = 0.0165);
MVP		0.13
MPC		0.15
ClinPred		0.018	T
GERP RS		2.5
Varity_R		0.063
gMVP		0.38

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;