2-85134023-G-T

Variant names:

• chr2-85134023-G-T
• rs201679633
• NM_031283.3:c.257G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_031283.3(TCF7L1):​c.257G>T​(p.Arg86Met) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,457,438 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R86T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TCF7L1 NM_031283.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.36
• Publications: 0 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

ENSG00000300535 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.814

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.257G>T	p.Arg86Met	missense	Exon 2 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.257G>T	p.Arg86Met	missense	Exon 2 of 12	ENSP00000282111.3	Q9HCS4
	TCF7L1	ENST00000922942.1		c.257G>T	p.Arg86Met	missense	Exon 2 of 12	ENSP00000593001.1
	TCF7L1	ENST00000868102.1		c.257G>T	p.Arg86Met	missense	Exon 2 of 12	ENSP00000538161.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457438 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 724954

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32916

American (AMR) AF: 0.00 AC: 0 AN: 44458

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25972

East Asian (EAS) AF: 0.00 AC: 0 AN: 39174

South Asian (SAS) AF: 0.00 AC: 0 AN: 85596

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53076

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5588

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110510

Other (OTH) AF: 0.00 AC: 0 AN: 60148

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	28
DANN	Benign	0.96
DEOGEN2	Uncertain	0.46	T
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		4.4
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-3.1	D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.60
MutPred		0.46		Loss of MoRF binding (P = 0.1951)
MVP		0.93
MPC		2.5
ClinPred		0.97	D
GERP RS		4.3
Varity_R		0.24
gMVP		0.62
Mutation Taster		=76/24	polymorphism

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: rs201679633; hg19: chr2-85361146;