chr10-112950906-T-A

Position:

• chr10-112950906-T-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001367943.1(TCF7L2):​c.150T>A​(p.Asn50Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,460,362 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: TCF7L2 NM_001367943.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.31

Genes affected

TCF7L2 (HGNC:11641): (transcription factor 7 like 2) This gene encodes a high mobility group (HMG) box-containing transcription factor that plays a key role in the Wnt signaling pathway. The protein has been implicated in blood glucose homeostasis. Genetic variants of this gene are associated with increased risk of type 2 diabetes. Several transcript variants encoding multiple different isoforms have been found for this gene.[provided by RefSeq, Oct 2010]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCF7L2	NM_001367943.1	c.150T>A	p.Asn50Lys	missense_variant	1/15	ENST00000355995.9
LOC124902502	XR_007062291.1	n.667A>T		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCF7L2	ENST00000355995.9	c.150T>A	p.Asn50Lys	missense_variant	1/15	1	NM_001367943.1
	ENST00000369391.3	n.200A>T		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1460362 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10 AN XY: 726330

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 21, 2023

The c.150T>A (p.N50K) alteration is located in exon 1 (coding exon 1) of the TCF7L2 gene. This alteration results from a T to A substitution at nucleotide position 150, causing the asparagine (N) at amino acid position 50 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T;T;D;.;T;.;.;.;.;T;.;T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Benign	0.34	N
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Uncertain	0.74	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	.;.;M;M;.;M;M;M;M;.;.;.
MutationTaster	Benign	0.98	D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-4.1	D;D;D;D;D;.;D;D;D;D;D;.
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0010	D;D;D;D;D;.;D;D;D;D;D;.
Sift4G	Benign	0.24	T;T;T;T;T;T;T;T;T;D;T;T
Polyphen		1.0, 0.99, 1.0	.;D;.;.;.;D;.;.;.;.;D;.
Vest4		0.47
MutPred		0.56		Gain of ubiquitination at N50 (P = 0.0069);Gain of ubiquitination at N50 (P = 0.0069);Gain of ubiquitination at N50 (P = 0.0069);Gain of ubiquitination at N50 (P = 0.0069);Gain of ubiquitination at N50 (P = 0.0069);Gain of ubiquitination at N50 (P = 0.0069);Gain of ubiquitination at N50 (P = 0.0069);Gain of ubiquitination at N50 (P = 0.0069);Gain of ubiquitination at N50 (P = 0.0069);Gain of ubiquitination at N50 (P = 0.0069);Gain of ubiquitination at N50 (P = 0.0069);Gain of ubiquitination at N50 (P = 0.0069);
MVP		0.98
MPC		1.7
ClinPred		0.99	D
GERP RS		2.9
Varity_R		0.83
gMVP		0.55

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-114710665;