Genetic Variant TFF2:p.Ser35Gly (chr21-42350007-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005423.5(TFF2):c.103A>G(p.Ser35Gly) 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 benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TFF2
NM_005423.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0700

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]

TFF2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13628116).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TFF2	NM_005423.5 link	c.103A>G	p.Ser35Gly	missense_variant	Exon 2 of 4	ENST00000291526.5	NP_005414.1	Q03403

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TFF2	ENST00000291526.5 link	c.103A>G	p.Ser35Gly	missense_variant	Exon 2 of 4	1	NM_005423.5	ENSP00000291526.4	Q03403
TFF2	ENST00000475297.1 link	n.233A>G		non_coding_transcript_exon_variant	Exon 3 of 5	3
TFF2	ENST00000463771.5 link	n.120-14A>G		intron_variant	Intron 1 of 3	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1447842

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

718638

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 27, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.103A>G (p.S35G) alteration is located in exon 2 (coding exon 2) of the TFF2 gene. This alteration results from a A to G substitution at nucleotide position 103, causing the serine (S) at amino acid position 35 to be replaced by a glycine (G). 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

-0.29

BayesDel_noAF

Benign

-0.66

CADD

Benign

7.4

DANN

Benign

0.91

DEOGEN2

Benign

0.37

Eigen

Benign

-0.93

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.49

M_CAP

Benign

0.015

MetaRNN

Benign

0.14

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.8

REVEL

Benign

0.025

Sift

Benign

0.24

Sift4G

Benign

0.35

Polyphen

0.019

Vest4

0.14

MutPred

0.36

Loss of stability (P = 0.0703);

MVP

0.25

MPC

0.37

ClinPred

0.085

GERP RS

0.66

Varity_R

0.063

gMVP

0.41

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over