Genetic Variant NM_003225.3:c.-2C>T (chr21-42366497-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_003225.3(TFF1):c.-2C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.145 in 1,608,450 control chromosomes in the GnomAD database, including 19,838 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.13 ( 1745 hom., cov: 32)

Exomes 𝑓: 0.15 ( 18093 hom. )

Consequence

TFF1
NM_003225.3 5_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.614

Publications

13 publications found

Variant links:

Genes affected

TFF1 (HGNC:11755): (trefoil factor 1) 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. This gene, which is expressed in the gastric mucosa, has also been studied because of its expression in human tumors. This gene and two other related trefoil family member genes are found in a cluster on chromosome 21. [provided by RefSeq, Jul 2008]

TFF1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.424 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TFF1	NM_003225.3 link	c.-2C>T		5_prime_UTR_variant	Exon 1 of 3	ENST00000291527.3	NP_003216.1	P04155

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TFF1	ENST00000291527.3 link	c.-2C>T		5_prime_UTR_variant	Exon 1 of 3	1	NM_003225.3	ENSP00000291527.2		P04155

Frequencies

GnomAD3 genomes

AF:

0.133

AC:

20201

AN:

152002

Hom.:

1751

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0751

Gnomad AMI

AF:

0.124

Gnomad AMR

AF:

0.141

Gnomad ASJ

AF:

0.119

Gnomad EAS

AF:

0.439

Gnomad SAS

AF:

0.204

Gnomad FIN

AF:

0.136

Gnomad MID

AF:

0.0854

Gnomad NFE

AF:

0.138

Gnomad OTH

AF:

0.149

GnomAD2 exomes

AF:

0.163

AC:

40172

AN:

246870

AF XY:

0.163

show subpopulations

Gnomad AFR exome

AF:

0.0718

Gnomad AMR exome

AF:

0.146

Gnomad ASJ exome

AF:

0.126

Gnomad EAS exome

AF:

0.447

Gnomad FIN exome

AF:

0.138

Gnomad NFE exome

AF:

0.136

Gnomad OTH exome

AF:

0.145

GnomAD4 exome

AF:

0.147

AC:

213733

AN:

1456330

Hom.:

18093

Cov.:

AF XY:

0.148

AC XY:

107161

AN XY:

724096

show subpopulations

African (AFR)

AF:

0.0700

AC:

2339

AN:

33392

American (AMR)

AF:

0.147

AC:

6530

AN:

44550

Ashkenazi Jewish (ASJ)

AF:

0.123

AC:

3190

AN:

26028

East Asian (EAS)

AF:

0.445

AC:

17629

AN:

39598

South Asian (SAS)

AF:

0.185

AC:

15916

AN:

85842

European-Finnish (FIN)

AF:

0.136

AC:

7227

AN:

53066

Middle Eastern (MID)

AF:

0.102

AC:

589

AN:

5754

European-Non Finnish (NFE)

AF:

0.136

AC:

151215

AN:

1108056

Other (OTH)

AF:

0.152

AC:

9098

AN:

60044

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

7826

15652

23478

31304

39130

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5646

11292

16938

22584

28230

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.133

AC:

20193

AN:

152120

Hom.:

1745

Cov.:

AF XY:

0.136

AC XY:

10135

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.0750

AC:

3117

AN:

41540

American (AMR)

AF:

0.140

AC:

2143

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.119

AC:

413

AN:

3468

East Asian (EAS)

AF:

0.439

AC:

2251

AN:

5132

South Asian (SAS)

AF:

0.204

AC:

981

AN:

4802

European-Finnish (FIN)

AF:

0.136

AC:

1439

AN:

10612

Middle Eastern (MID)

AF:

0.0816

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.138

AC:

9401

AN:

67970

Other (OTH)

AF:

0.148

AC:

312

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

835

1670

2505

3340

4175

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

232

464

696

928

1160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.127

Hom.:

2121

Bravo

AF:

0.130

Asia WGS

AF:

0.268

AC:

930

AN:

3478

EpiCase

AF:

0.131

EpiControl

AF:

0.131

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

1.0

(source)

DANN

Benign

0.70

PhyloP100

-0.61

PromoterAI

-0.054

Neutral

(source)

Mutation Taster

=300/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over