21-42350945-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_005423.5(TFF2):​c.13G>A​(p.Asp5Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000062 in 1,613,980 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 1 hom., cov: 33)
Exomes 𝑓: 0.000063 ( 0 hom. )

Consequence

TFF2
NM_005423.5 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.603
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.029005617).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TFF2NM_005423.5 linkc.13G>A p.Asp5Asn missense_variant Exon 1 of 4 ENST00000291526.5 NP_005414.1 Q03403

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TFF2ENST00000291526.5 linkc.13G>A p.Asp5Asn missense_variant Exon 1 of 4 1 NM_005423.5 ENSP00000291526.4 Q03403
TFF2ENST00000463771.5 linkn.53G>A non_coding_transcript_exon_variant Exon 1 of 4 5
TFF2ENST00000475297.1 linkn.50G>A non_coding_transcript_exon_variant Exon 1 of 5 3

Frequencies

GnomAD3 genomes
AF:
0.0000525
AC:
8
AN:
152246
Hom.:
1
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00103
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000797
AC:
20
AN:
250902
Hom.:
0
AF XY:
0.000118
AC XY:
16
AN XY:
135666
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000524
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.000164
GnomAD4 exome
AF:
0.0000629
AC:
92
AN:
1461616
Hom.:
0
Cov.:
31
AF XY:
0.0000770
AC XY:
56
AN XY:
727138
show subpopulations
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:
0.000685
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000207
Gnomad4 OTH exome
AF:
0.000132
GnomAD4 genome
AF:
0.0000525
AC:
8
AN:
152364
Hom.:
1
Cov.:
33
AF XY:
0.0000805
AC XY:
6
AN XY:
74506
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00104
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000986
Hom.:
0
Bravo
AF:
0.0000416
ExAC
AF:
0.0000741
AC:
9
Asia WGS
AF:
0.000866
AC:
3
AN:
3478
EpiCase
AF:
0.000109
EpiControl
AF:
0.00

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jan 22, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.13G>A (p.D5N) alteration is located in exon 1 (coding exon 1) of the TFF2 gene. This alteration results from a G to A substitution at nucleotide position 13, causing the aspartic acid (D) at amino acid position 5 to be replaced by an asparagine (N). 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
Benign
0.12
BayesDel_addAF
Benign
-0.59
T
BayesDel_noAF
Benign
-0.74
CADD
Benign
11
DANN
Benign
0.96
DEOGEN2
Benign
0.15
T
Eigen
Benign
-0.85
Eigen_PC
Benign
-0.88
FATHMM_MKL
Benign
0.051
N
LIST_S2
Benign
0.53
T
M_CAP
Benign
0.0061
T
MetaRNN
Benign
0.029
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.6
L
PrimateAI
Uncertain
0.51
T
PROVEAN
Benign
-0.55
N
REVEL
Benign
0.021
Sift
Benign
0.47
T
Sift4G
Benign
0.47
T
Polyphen
0.067
B
Vest4
0.081
MVP
0.20
MPC
0.33
ClinPred
0.019
T
GERP RS
2.4
Varity_R
0.030
gMVP
0.58

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs749668261; hg19: chr21-43771054; API