chr2-85133718-G-A

Variant names:

• chr2-85133718-G-A
• rs534725385
• NM_031283.3:c.34G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_031283.3(TCF7L1):​c.34G>A​(p.Gly12Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00792 in 1,154,898 control chromosomes in the GnomAD database, including 94 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0080 (16 hom., cov: 32)
  • Exomes 𝑓: 0.0079 (78 hom.)
• Consequence: TCF7L1 NM_031283.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.26
• Publications: 5 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]

ENSG00000300535 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0069305897).
• BP6: Variant 2-85133718-G-A is Benign according to our data. Variant chr2-85133718-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2651091.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 1182 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.34G>A	p.Gly12Ser	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.34G>A	p.Gly12Ser	missense	Exon 1 of 12	ENSP00000282111.3	Q9HCS4
	TCF7L1	ENST00000922942.1		c.34G>A	p.Gly12Ser	missense	Exon 1 of 12	ENSP00000593001.1
	TCF7L1	ENST00000868102.1		c.34G>A	p.Gly12Ser	missense	Exon 1 of 12	ENSP00000538161.1

Frequencies

GnomAD3 genomes AF: 0.00798 AC: 1182 AN: 148128 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.00144

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.00188

Gnomad ASJ AF: 0.00410

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00559

Gnomad FIN AF: 0.0484

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00886

Gnomad OTH AF: 0.00686

GnomAD2 exomes AF: 0.00936 AC: 9 AN: 962 AF XY: 0.0106

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad FIN exome AF: 0.0183

Gnomad NFE exome AF: 0.00787

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00791 AC: 7961 AN: 1006662 Hom.: 78 Cov.: 31 AF XY: 0.00773 AC XY: 3675 AN XY: 475128

African (AFR) AF: 0.000639 AC: 13 AN: 20348

American (AMR) AF: 0.00119 AC: 7 AN: 5906

Ashkenazi Jewish (ASJ) AF: 0.00369 AC: 41 AN: 11106

East Asian (EAS) AF: 0.00 AC: 0 AN: 19274

South Asian (SAS) AF: 0.00461 AC: 87 AN: 18856

European-Finnish (FIN) AF: 0.0554 AC: 960 AN: 17314

Middle Eastern (MID) AF: 0.000794 AC: 2 AN: 2520

European-Non Finnish (NFE) AF: 0.00753 AC: 6573 AN: 873052

Other (OTH) AF: 0.00726 AC: 278 AN: 38286

GnomAD4 genome AF: 0.00797 AC: 1182 AN: 148236 Hom.: 16 Cov.: 32 AF XY: 0.00993 AC XY: 718 AN XY: 72276

African (AFR) AF: 0.00144 AC: 59 AN: 41092

American (AMR) AF: 0.00188 AC: 28 AN: 14906

Ashkenazi Jewish (ASJ) AF: 0.00410 AC: 14 AN: 3418

East Asian (EAS) AF: 0.00 AC: 0 AN: 5106

South Asian (SAS) AF: 0.00559 AC: 27 AN: 4826

European-Finnish (FIN) AF: 0.0484 AC: 437 AN: 9024

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00886 AC: 590 AN: 66598

Other (OTH) AF: 0.00678 AC: 14 AN: 2064

Alfa AF: 0.0106 Hom.: 3

Bravo AF: 0.00467

ExAC AF: 0.00190 AC: 7

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	15
DANN	Benign	0.89
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.48	T
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.0069	T
MetaSVM	Uncertain	0.34	D
MutationAssessor	Benign	0.55	N
PhyloP100		2.3
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.28	N
REVEL	Uncertain	0.35
Sift	Benign	0.31	T
Sift4G	Benign	0.57	T
Polyphen		0.039	B
Vest4		0.31
MVP		0.88
MPC		1.2
ClinPred		0.058	T
GERP RS		1.8
PromoterAI		-0.0080	Neutral
Varity_R		0.080
gMVP		0.25
Mutation Taster		=93/7	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: rs534725385; hg19: chr2-85360841;