21-42313518-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

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
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.96

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 779476.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TFF3	NM_003226.4	c.196G>A	p.Val66Met	missense_variant	2/3	ENST00000518498.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TFF3	ENST00000518498.3	c.196G>A	p.Val66Met	missense_variant	2/3	1	NM_003226.4	P1
TFF3	ENST00000398431.2	c.204G>A	p.Glu68=	synonymous_variant	2/3	3
TFF3	ENST00000489676.1	n.169G>A		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.00354 AC: 538 AN: 152162 Hom.: 1 Cov.: 32

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

GnomAD3 exomes AF: 0.00432 AC: 1075 AN: 248568 Hom.: 5 AF XY: 0.00469 AC XY: 630 AN XY: 134454

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 SAS exome AF: 0.00269

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.: 31 Cov.: 31 AF XY: 0.00541 AC XY: 3923 AN XY: 725194

Gnomad4 AFR exome AF: 0.000601

Gnomad4 AMR exome AF: 0.00288

Gnomad4 ASJ exome AF: 0.00295

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00281

Gnomad4 FIN exome AF: 0.00169

Gnomad4 NFE exome AF: 0.00629

Gnomad4 OTH exome AF: 0.00499

GnomAD4 genome AF: 0.00353 AC: 537 AN: 152280 Hom.: 1 Cov.: 32 AF XY: 0.00344 AC XY: 256 AN XY: 74464

Gnomad4 AFR AF: 0.00135

Gnomad4 AMR AF: 0.00327

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00141

Gnomad4 NFE AF: 0.00570

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00569 Hom.: 2

Bravo AF: 0.00349

TwinsUK AF: 0.00755 AC: 28

ALSPAC AF: 0.00597 AC: 23

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00605 AC: 52

ExAC AF: 0.00452 AC: 549

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 25, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.10
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.010	T;T
MetaSVM	Uncertain	-0.24	T
MutationTaster	Benign	0.94	D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-2.3	N;.
REVEL	Uncertain	0.32
Sift	Uncertain	0.0020	D;.
Sift4G	Uncertain	0.0040	D;D
Vest4		0.65
MVP		0.37
MPC		0.95
ClinPred		0.018	T
GERP RS		4.4
Varity_R		0.43
gMVP		0.67

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

LitVar

Other links and lift over

dbSNP: rs118095917; hg19: chr21-43733628; COSMIC: COSV99063152;