NM_001367943.1:c.84G>A

Variant names:

• chr10-112950840-G-A
• rs373425129
• NM_001367943.1:c.84G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Moderate BP6_Moderate BP7 BS2

The NM_001367943.1(TCF7L2):​c.84G>A​(p.Glu28Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000852 in 1,608,438 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00042 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000050 (0 hom.)
• Consequence: TCF7L2 NM_001367943.1 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.01
• Publications: 0 publications found

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]

TCF7L2 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia
• intellectual disability

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• congenital glaucoma

  Inheritance: Unknown Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000233547 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 10-112950840-G-A is Benign according to our data. Variant chr10-112950840-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 708494.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=3.01 with no splicing effect.
• BS2: High AC in GnomAd4 at 64 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001367943.1. 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
	TCF7L2	NM_001367943.1	MANE Select	c.84G>A	p.Glu28Glu	synonymous	Exon 1 of 15	NP_001354872.1	Q9NQB0-1
	TCF7L2	NM_001146274.2		c.84G>A	p.Glu28Glu	synonymous	Exon 1 of 14	NP_001139746.1	Q9NQB0-7
	TCF7L2	NM_030756.5		c.84G>A	p.Glu28Glu	synonymous	Exon 1 of 14	NP_110383.2	Q9NQB0-8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCF7L2	ENST00000355995.9	TSL:1 MANE Select	c.84G>A	p.Glu28Glu	synonymous	Exon 1 of 15	ENSP00000348274.4	Q9NQB0-1
	TCF7L2	ENST00000627217.3	TSL:1	c.84G>A	p.Glu28Glu	synonymous	Exon 1 of 14	ENSP00000486891.1	Q9NQB0-7
	TCF7L2	ENST00000369397.8	TSL:1	c.84G>A	p.Glu28Glu	synonymous	Exon 1 of 14	ENSP00000358404.4	Q9NQB0-8

Frequencies

GnomAD3 genomes AF: 0.000421 AC: 64 AN: 152112 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00142

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000124 AC: 30 AN: 242200 AF XY: 0.0000917

Gnomad AFR exome AF: 0.00182

Gnomad AMR exome AF: 0.0000887

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000501 AC: 73 AN: 1456210 Hom.: 0 Cov.: 32 AF XY: 0.0000456 AC XY: 33 AN XY: 723818

African (AFR) AF: 0.00189 AC: 63 AN: 33410

American (AMR) AF: 0.0000679 AC: 3 AN: 44164

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25712

East Asian (EAS) AF: 0.00 AC: 0 AN: 39624

South Asian (SAS) AF: 0.00 AC: 0 AN: 85088

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52988

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5654

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109338

Other (OTH) AF: 0.000116 AC: 7 AN: 60232

GnomAD4 genome AF: 0.000420 AC: 64 AN: 152228 Hom.: 0 Cov.: 29 AF XY: 0.000349 AC XY: 26 AN XY: 74428

African (AFR) AF: 0.00142 AC: 59 AN: 41548

American (AMR) AF: 0.000262 AC: 4 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000453

ClinVar

ClinVar submissions

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
BayesDel_noAF	Benign	-0.39
CADD	Benign	19
DANN	Benign	0.95
PhyloP100		3.0
PromoterAI		0.12	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs373425129; hg19: chr10-114710599;