chr5-134115385-A-C

Variant names:

• chr5-134115385-A-C
• rs372762533
• NM_003202.5:c.314A>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003202.5(TCF7):​c.314A>C​(p.Asp105Ala) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: TCF7 NM_003202.5 missense, splice_region
• Scores: Splicing: ADA: 0.001467
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.23

Genes affected

TCF7 (HGNC:11639): (transcription factor 7) This gene encodes a member of the T-cell factor/lymphoid enhancer-binding factor family of high mobility group (HMG) box transcriptional activators. This gene is expressed predominantly in T-cells and plays a critical role in natural killer cell and innate lymphoid cell development. The encoded protein forms a complex with beta-catenin and activates transcription through a Wnt/beta-catenin signaling pathway. Mice with a knockout of this gene are viable and fertile, but display a block in T-lymphocyte differentiation. Alternative splicing results in multiple transcript variants. Naturally-occurring isoforms lacking the N-terminal beta-catenin interaction domain may act as dominant negative regulators of Wnt signaling. [provided by RefSeq, Oct 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCF7	NM_003202.5	c.314A>C	p.Asp105Ala	missense_variant, splice_region_variant	Exon 2 of 10	ENST00000342854.10	NP_003193.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCF7	ENST00000342854.10	c.314A>C	p.Asp105Ala	missense_variant, splice_region_variant	Exon 2 of 10	1	NM_003202.5	ENSP00000340347.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000345 AC: 5 AN: 1448034 Hom.: 1 Cov.: 32 AF XY: 0.00000695 AC XY: 5 AN XY: 719274

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000128

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.35	.;T
Eigen	Benign	-0.041
Eigen_PC	Benign	0.028
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.67	T;T
M_CAP	Pathogenic	0.95	D
MetaRNN	Uncertain	0.66	D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Benign	1.4	L;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-2.2	N;N
REVEL	Uncertain	0.53
Sift	Uncertain	0.023	D;D
Sift4G	Benign	0.14	T;T
Polyphen		0.34	B;.
Vest4		0.52
MutPred		0.52		Loss of solvent accessibility (P = 0.1279);Loss of solvent accessibility (P = 0.1279);
MVP		0.97
MPC		0.26
ClinPred		0.56	D
GERP RS		3.7
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0015
dbscSNV1_RF	Benign	0.10
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: rs372762533; hg19: chr5-133451076;