Genetic Variant TFF3:c.-157C>G (chr21-42315531-G-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_003226.4(TFF3):c.-157C>G variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00193 in 1,539,168 control chromosomes in the GnomAD database, including 43 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 0.0080 ( 13 hom., cov: 33)

Exomes 𝑓: 0.0013 ( 30 hom. )

Consequence

TFF3
NM_003226.4 upstream_gene

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.204

Publications

3 publications found

Variant links:

Genes affected

TFF3 (HGNC:11757): (trefoil factor 3) 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 is expressed in goblet cells of the intestines and colon. This gene and two other related trefoil family member genes are found in a cluster on chromosome 21. [provided by RefSeq, Jul 2008]

TFF3 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=-0.82).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00798 (1215/152320) while in subpopulation AFR AF = 0.0247 (1026/41570). AF 95% confidence interval is 0.0234. There are 13 homozygotes in GnomAd4. There are 586 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TFF3	NM_003226.4 link	c.-157C>G		upstream_gene_variant		ENST00000518498.3	NP_003217.4	Q07654

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TFF3	ENST00000518498.3 link	c.-157C>G		upstream_gene_variant		1	NM_003226.4	ENSP00000430690.2		Q07654
TFF3	ENST00000398431.2 link	c.-196C>G		upstream_gene_variant		3		ENSP00000381462.2		H7BYT0

Frequencies

GnomAD3 genomes

AF:

0.00796

AC:

1211

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0247

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00713

Gnomad ASJ

AF:

0.00779

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000353

Gnomad OTH

AF:

0.00813

GnomAD2 exomes

AF:

0.00287

AC:

720

AN:

250884

AF XY:

0.00260

show subpopulations

Gnomad AFR exome

AF:

0.0274

Gnomad AMR exome

AF:

0.00324

Gnomad ASJ exome

AF:

0.00559

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000309

Gnomad OTH exome

AF:

0.00180

GnomAD4 exome

AF:

0.00126

AC:

1750

AN:

1386848

Hom.:

Cov.:

AF XY:

0.00128

AC XY:

890

AN XY:

694126

show subpopulations

African (AFR)

AF:

0.0296

AC:

942

AN:

31852

American (AMR)

AF:

0.00328

AC:

146

AN:

44496

Ashkenazi Jewish (ASJ)

AF:

0.00571

AC:

146

AN:

25572

East Asian (EAS)

AF:

0.00

AC:

AN:

39212

South Asian (SAS)

AF:

0.00245

AC:

206

AN:

84104

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52994

Middle Eastern (MID)

AF:

0.00551

AC:

AN:

5622

European-Non Finnish (NFE)

AF:

0.000137

AC:

143

AN:

1045296

Other (OTH)

AF:

0.00236

AC:

136

AN:

57700

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

185

278

370

463

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00798

AC:

1215

AN:

152320

Hom.:

Cov.:

AF XY:

0.00787

AC XY:

586

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.0247

AC:

1026

AN:

41570

American (AMR)

AF:

0.00713

AC:

109

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00779

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00228

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000353

AC:

AN:

68032

Other (OTH)

AF:

0.00804

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

116

173

231

289

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00322

Hom.:

Bravo

AF:

0.00900

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000356

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

2.2

(source)

DANN

Benign

0.76

PhyloP100

-0.20

PromoterAI

-0.027

Neutral

(source)

Mutation Taster

=300/0

polymorphism

(source)

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

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chr21-42315531-G-C

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