chr2-85283531-T-A

Position:

• chr2-85283531-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000282111.4(TCF7L1):​c.478T>A​(p.Ser160Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00227 in 1,614,112 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0099 (26 hom., cov: 31)
  • Exomes 𝑓: 0.0015 (19 hom.)
• Consequence: TCF7L1 ENST00000282111.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0630

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007574886).
• BP6: Variant 2-85283531-T-A is Benign according to our data. Variant chr2-85283531-T-A is described in ClinVar as [Benign]. Clinvar id is 784988.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0099 (1507/152236) while in subpopulation AFR AF= 0.0338 (1402/41524). AF 95% confidence interval is 0.0323. There are 26 homozygotes in gnomad4. There are 730 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1507 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCF7L1	NM_031283.3	c.478T>A	p.Ser160Thr	missense_variant	4/12	ENST00000282111.4	NP_112573.1
TCF7L1	XM_006712109.3	c.478T>A	p.Ser160Thr	missense_variant	4/12		XP_006712172.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCF7L1	ENST00000282111.4	c.478T>A	p.Ser160Thr	missense_variant	4/12	1	NM_031283.3	ENSP00000282111.3
TCF7L1	ENST00000442813.1	c.28T>A	p.Ser10Thr	missense_variant	5/6	5		ENSP00000388984.1

Frequencies

GnomAD3 genomes AF: 0.00987 AC: 1502 AN: 152118 Hom.: 27 Cov.: 31

Gnomad AFR AF: 0.0337

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00347

Gnomad SAS AF: 0.00332

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00332 AC: 834 AN: 251480 Hom.: 10 AF XY: 0.00283 AC XY: 385 AN XY: 135910

Gnomad AFR exome AF: 0.0315

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.00609

Gnomad SAS exome AF: 0.00402

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00148 AC: 2165 AN: 1461876 Hom.: 19 Cov.: 31 AF XY: 0.00144 AC XY: 1049 AN XY: 727238

Gnomad4 AFR exome AF: 0.0352

Gnomad4 AMR exome AF: 0.00168

Gnomad4 ASJ exome AF: 0.000497

Gnomad4 EAS exome AF: 0.00322

Gnomad4 SAS exome AF: 0.00414

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000187

Gnomad4 OTH exome AF: 0.00311

GnomAD4 genome AF: 0.00990 AC: 1507 AN: 152236 Hom.: 26 Cov.: 31 AF XY: 0.00981 AC XY: 730 AN XY: 74442

Gnomad4 AFR AF: 0.0338

Gnomad4 AMR AF: 0.00320

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00347

Gnomad4 SAS AF: 0.00332

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00193 Hom.: 6

Bravo AF: 0.0106

ESP6500AA AF: 0.0304 AC: 134

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00395 AC: 480

Asia WGS AF: 0.00924 AC: 32 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 09, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	14
DANN	Benign	0.91
DEOGEN2	Benign	0.15	T;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.094
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.74	T;T
MetaRNN	Benign	0.0076	T;T
MetaSVM	Uncertain	0.053	D
MutationAssessor	Benign	1.5	L;.
MutationTaster	Benign	0.97	N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.81	N;D
REVEL	Uncertain	0.36
Sift	Benign	0.034	D;T
Sift4G	Benign	0.19	T;T
Polyphen		0.39	B;.
Vest4		0.31
MVP		0.71
MPC		0.23
ClinPred		0.015	T
GERP RS		3.1
Varity_R		0.088
gMVP		0.22

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: rs115942112; hg19: chr2-85510654;