rs11547160

Variant names:

• chr2-85309292-G-A
• rs11547160
• NM_031283.3:c.1597G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_031283.3(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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G533W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.038 (172 hom., cov: 31)
  • Exomes 𝑓: 0.058 (2783 hom.)
• Consequence: TCF7L1 NM_031283.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.00
• Publications: 18 publications found

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]

TCF7L1 Gene-Disease associations (from GenCC):

• combined pituitary hormone deficiencies, genetic form

  Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031283.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCF7L1	NM_031283.3	MANE Select	c.1597G>A	p.Gly533Arg	missense	Exon 12 of 12	NP_112573.1	Q9HCS4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCF7L1	ENST00000282111.4	TSL:1 MANE Select	c.1597G>A	p.Gly533Arg	missense	Exon 12 of 12	ENSP00000282111.3	Q9HCS4
	TCF7L1	ENST00000922942.1		c.1615G>A	p.Gly539Arg	missense	Exon 12 of 12	ENSP00000593001.1
	TCF7L1	ENST00000868102.1		c.1600G>A	p.Gly534Arg	missense	Exon 12 of 12	ENSP00000538161.1

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

GnomAD2 exomes AF: 0.0417 AC: 10377 AN: 248750 AF XY: 0.0438

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 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

African (AFR) AF: 0.00944 AC: 316 AN: 33476

American (AMR) AF: 0.0278 AC: 1245 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.0168 AC: 440 AN: 26120

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39700

South Asian (SAS) AF: 0.0577 AC: 4981 AN: 86252

European-Finnish (FIN) AF: 0.0202 AC: 1069 AN: 52888

Middle Eastern (MID) AF: 0.0246 AC: 142 AN: 5768

European-Non Finnish (NFE) AF: 0.0662 AC: 73600 AN: 1111892

Other (OTH) AF: 0.0499 AC: 3012 AN: 60372

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

African (AFR) AF: 0.0117 AC: 486 AN: 41518

American (AMR) AF: 0.0351 AC: 537 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0150 AC: 52 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.0496 AC: 238 AN: 4802

European-Finnish (FIN) AF: 0.0164 AC: 174 AN: 10590

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0619 AC: 4209 AN: 68010

Other (OTH) AF: 0.0356 AC: 75 AN: 2108

Alfa AF: 0.0521 Hom.: 900

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 v4.9

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
PhyloP100		1.0
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
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

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