2-85309292-G-A

Position:

• chr2-85309292-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000282111.4(TCF7L1):​c.1597G>A​(p.Gly533Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0562 in 1,613,332 control chromosomes in the GnomAD database, including 2,955 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.038 (172 hom., cov: 31)
  • Exomes 𝑓: 0.058 (2783 hom.)
• Consequence: TCF7L1 ENST00000282111.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.00

Genes affected

TCF7L1 (HGNC:11640): (transcription factor 7 like 1) This gene encodes a member of the T cell factor/lymphoid enhancer factor family of transcription factors. These transcription factors are activated by beta catenin, mediate the Wnt signaling pathway and are antagonized by the transforming growth factor beta signaling pathway. The encoded protein contains a high mobility group-box DNA binding domain and participates in the regulation of cell cycle genes and cellular senescence. [provided by RefSeq, Nov 2010]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018329918).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0603 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCF7L1	NM_031283.3	c.1597G>A	p.Gly533Arg	missense_variant	12/12	ENST00000282111.4	NP_112573.1
TCF7L1	XM_006712109.3	c.1600G>A	p.Gly534Arg	missense_variant	12/12		XP_006712172.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCF7L1	ENST00000282111.4	c.1597G>A	p.Gly533Arg	missense_variant	12/12	1	NM_031283.3	ENSP00000282111	P1

Frequencies

GnomAD3 genomes AF: 0.0383 AC: 5819 AN: 152040 Hom.: 172 Cov.: 31

Gnomad AFR AF: 0.0117

Gnomad AMI AF: 0.0440

Gnomad AMR AF: 0.0351

Gnomad ASJ AF: 0.0150

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0497

Gnomad FIN AF: 0.0164

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0619

Gnomad OTH AF: 0.0360

GnomAD3 exomes AF: 0.0417 AC: 10377 AN: 248750 Hom.: 296 AF XY: 0.0438 AC XY: 5913 AN XY: 134880

Gnomad AFR exome AF: 0.0108

Gnomad AMR exome AF: 0.0267

Gnomad ASJ exome AF: 0.0169

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0560

Gnomad FIN exome AF: 0.0199

Gnomad NFE exome AF: 0.0600

Gnomad OTH exome AF: 0.0430

GnomAD4 exome AF: 0.0580 AC: 84813 AN: 1461174 Hom.: 2783 Cov.: 32 AF XY: 0.0582 AC XY: 42338 AN XY: 726914

Gnomad4 AFR exome AF: 0.00944

Gnomad4 AMR exome AF: 0.0278

Gnomad4 ASJ exome AF: 0.0168

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.0577

Gnomad4 FIN exome AF: 0.0202

Gnomad4 NFE exome AF: 0.0662

Gnomad4 OTH exome AF: 0.0499

GnomAD4 genome AF: 0.0382 AC: 5816 AN: 152158 Hom.: 172 Cov.: 31 AF XY: 0.0366 AC XY: 2721 AN XY: 74372

Gnomad4 AFR AF: 0.0117

Gnomad4 AMR AF: 0.0351

Gnomad4 ASJ AF: 0.0150

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0496

Gnomad4 FIN AF: 0.0164

Gnomad4 NFE AF: 0.0619

Gnomad4 OTH AF: 0.0356

Alfa AF: 0.0541 Hom.: 671

Bravo AF: 0.0373

TwinsUK AF: 0.0685 AC: 254

ALSPAC AF: 0.0646 AC: 249

ESP6500AA AF: 0.0134 AC: 59

ESP6500EA AF: 0.0621 AC: 534

ExAC AF: 0.0420 AC: 5094

Asia WGS AF: 0.0170 AC: 59 AN: 3478

EpiCase AF: 0.0577

EpiControl AF: 0.0583

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.083	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0018	T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	0.86	D
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.77	N
REVEL	Benign	0.21
Sift	Uncertain	0.010	D
Sift4G	Benign	0.53	T
Polyphen		0.12	B
Vest4		0.049
MutPred		0.11		Gain of MoRF binding (P = 0.0114);
MPC		0.34
ClinPred		0.0041	T
GERP RS		0.084
Varity_R		0.079
gMVP		0.45

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: rs11547160; hg19: chr2-85536415; COSMIC: COSV56404291; COSMIC: COSV56404291;