21-42349974-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_005423.5(TFF2):​c.136G>A​(p.Gly46Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

TFF2
NM_005423.5 missense

Scores

4
8
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.67
Variant links:
Genes affected
TFF2 (HGNC:11756): (trefoil factor 2) Members of the trefoil family are characterized by having at least one copy of the trefoil motif, a 40-amino acid domain that contains three conserved disulfides. They are stable secretory proteins expressed in gastrointestinal mucosa. Their functions are not defined, but they may protect the mucosa from insults, stabilize the mucus layer and affect healing of the epithelium. The encoded protein inhibits gastric acid secretion. This gene and two other related trefoil family member genes are found in a cluster on chromosome 21. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.91

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TFF2NM_005423.5 linkc.136G>A p.Gly46Arg missense_variant Exon 2 of 4 ENST00000291526.5 NP_005414.1 Q03403

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TFF2ENST00000291526.5 linkc.136G>A p.Gly46Arg missense_variant Exon 2 of 4 1 NM_005423.5 ENSP00000291526.4 Q03403
TFF2ENST00000463771.5 linkn.139G>A non_coding_transcript_exon_variant Exon 2 of 4 5
TFF2ENST00000475297.1 linkn.266G>A non_coding_transcript_exon_variant Exon 3 of 5 3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jun 07, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.136G>A (p.G46R) alteration is located in exon 2 (coding exon 2) of the TFF2 gene. This alteration results from a G to A substitution at nucleotide position 136, causing the glycine (G) at amino acid position 46 to be replaced by an arginine (R). 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
Uncertain
0.49
BayesDel_addAF
Uncertain
0.023
T
BayesDel_noAF
Benign
-0.20
CADD
Uncertain
23
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.89
D
Eigen
Uncertain
0.43
Eigen_PC
Uncertain
0.27
FATHMM_MKL
Benign
0.27
N
LIST_S2
Benign
0.60
T
M_CAP
Benign
0.044
D
MetaRNN
Pathogenic
0.91
D
MetaSVM
Benign
-0.44
T
MutationAssessor
Uncertain
2.3
M
PrimateAI
Uncertain
0.59
T
PROVEAN
Pathogenic
-7.1
D
REVEL
Benign
0.28
Sift
Uncertain
0.013
D
Sift4G
Uncertain
0.012
D
Polyphen
1.0
D
Vest4
0.78
MutPred
0.73
Gain of solvent accessibility (P = 0.0037);
MVP
0.76
MPC
1.2
ClinPred
0.99
D
GERP RS
4.8
Varity_R
0.60
gMVP
0.73

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.13
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: chr21-43770083; API