Genetic Variant NM_003226.4:c.196G>A (chr21-42313518-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_003226.4(TFF3):c.196G>A(p.Val66Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00522 in 1,610,076 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0035 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0054 ( 31 hom. )

Consequence

TFF3
NM_003226.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.96

Publications

10 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010167301).

BP6

Variant 21-42313518-C-T is Benign according to our data. Variant chr21-42313518-C-T is described in ClinVar as Benign. ClinVar VariationId is 779476.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAdExome4 at 31 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003226.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFF3	NM_003226.4	MANE Select	c.196G>A	p.Val66Met	missense	Exon 2 of 3	NP_003217.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TFF3	ENST00000518498.3	TSL:1 MANE Select	c.196G>A	p.Val66Met	missense	Exon 2 of 3	ENSP00000430690.2	Q07654
TFF3	ENST00000891173.1		c.196G>A	p.Val66Met	missense	Exon 2 of 4	ENSP00000561232.1
TFF3	ENST00000398431.2	TSL:3	c.201G>A	p.Glu67Glu	synonymous	Exon 2 of 3	ENSP00000381462.2	H7BYT0

Frequencies

GnomAD3 genomes

AF:

0.00354

AC:

538

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00135

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00327

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00141

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00572

Gnomad OTH

AF:

0.00334

GnomAD2 exomes

AF:

0.00432

AC:

1075

AN:

248568

AF XY:

0.00469

show subpopulations

Gnomad AFR exome

AF:

0.00130

Gnomad AMR exome

AF:

0.00335

Gnomad ASJ exome

AF:

0.00350

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00153

Gnomad NFE exome

AF:

0.00672

Gnomad OTH exome

AF:

0.00567

GnomAD4 exome

AF:

0.00540

AC:

7875

AN:

1457796

Hom.:

Cov.:

AF XY:

0.00541

AC XY:

3923

AN XY:

725194

show subpopulations

African (AFR)

AF:

0.000601

AC:

AN:

33298

American (AMR)

AF:

0.00288

AC:

128

AN:

44442

Ashkenazi Jewish (ASJ)

AF:

0.00295

AC:

AN:

26066

East Asian (EAS)

AF:

0.00

AC:

AN:

39516

South Asian (SAS)

AF:

0.00281

AC:

241

AN:

85780

European-Finnish (FIN)

AF:

0.00169

AC:

AN:

53378

Middle Eastern (MID)

AF:

0.00652

AC:

AN:

4142

European-Non Finnish (NFE)

AF:

0.00629

AC:

6992

AN:

1111036

Other (OTH)

AF:

0.00499

AC:

300

AN:

60138

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

461

922

1384

1845

2306

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

266

532

798

1064

1330

<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:

0.00353

AC:

537

AN:

152280

Hom.:

Cov.:

AF XY:

0.00344

AC XY:

256

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.00135

AC:

AN:

41560

American (AMR)

AF:

0.00327

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

3468

East Asian (EAS)

AF:

0.000194

AC:

AN:

5154

South Asian (SAS)

AF:

0.00145

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00141

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00570

AC:

388

AN:

68014

Other (OTH)

AF:

0.00331

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.518

Heterozygous variant carriers

123

154

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00544

Hom.:

Bravo

AF:

0.00349

TwinsUK

AF:

0.00755

AC:

ALSPAC

AF:

0.00597

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00605

AC:

ExAC

AF:

0.00452

AC:

549

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.90

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.010

MetaSVM

Uncertain

-0.24

PhyloP100

3.0

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-2.3

REVEL

Uncertain

0.32

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0040

Vest4

0.65

MVP

0.37

MPC

0.95

ClinPred

0.018

GERP RS

4.4

Varity_R

0.43

gMVP

0.67

Mutation Taster

=89/11

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over