NM_031283.3:c.7C>A

Variant names:

• chr2-85133691-C-A
• rs1334136297
• NM_031283.3:c.7C>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_031283.3(TCF7L1):​c.7C>A​(p.Gln3Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000291 in 998,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000012 (0 hom.)
• Consequence: TCF7L1 NM_031283.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0800
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13697189).
• BS2: High AC in GnomAd4 at 28 AD gene.

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.7C>A	p.Gln3Lys	missense	Exon 1 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.7C>A	p.Gln3Lys	missense	Exon 1 of 12	ENSP00000282111.3	Q9HCS4
	TCF7L1	ENST00000922942.1		c.7C>A	p.Gln3Lys	missense	Exon 1 of 12	ENSP00000593001.1
	TCF7L1	ENST00000868102.1		c.7C>A	p.Gln3Lys	missense	Exon 1 of 12	ENSP00000538161.1

Frequencies

GnomAD3 genomes AF: 0.000198 AC: 28 AN: 141312 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000181

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00145

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000117 AC: 1 AN: 856868 Hom.: 0 Cov.: 20 AF XY: 0.00 AC XY: 0 AN XY: 399454

African (AFR) AF: 0.0000611 AC: 1 AN: 16362

American (AMR) AF: 0.00 AC: 0 AN: 1864

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5898

East Asian (EAS) AF: 0.00 AC: 0 AN: 4962

South Asian (SAS) AF: 0.00 AC: 0 AN: 17398

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4130

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1782

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 775634

Other (OTH) AF: 0.00 AC: 0 AN: 28838

GnomAD4 genome AF: 0.000198 AC: 28 AN: 141312 Hom.: 0 Cov.: 32 AF XY: 0.000248 AC XY: 17 AN XY: 68594

African (AFR) AF: 0.000181 AC: 7 AN: 38686

American (AMR) AF: 0.00145 AC: 21 AN: 14466

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3336

East Asian (EAS) AF: 0.00 AC: 0 AN: 4998

South Asian (SAS) AF: 0.00 AC: 0 AN: 4660

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7822

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 304

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 64292

Other (OTH) AF: 0.00 AC: 0 AN: 1928

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000831

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.052	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.073	N
LIST_S2	Benign	0.44	T
M_CAP	Pathogenic	0.60	D
MetaRNN	Benign	0.14	T
MetaSVM	Uncertain	0.54	D
MutationAssessor	Benign	1.1	L
PhyloP100		-0.080
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.011	D
Polyphen		0.0010	B
Vest4		0.17
MutPred		0.59		Gain of ubiquitination at Q3 (P = 0.0104)
MVP		0.47
MPC		1.5
ClinPred		0.15	T
GERP RS		2.4
PromoterAI		-0.026	Neutral
Varity_R		0.58
gMVP		0.46
Mutation Taster		=95/5	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: rs1334136297; hg19: chr2-85360814;