21-42347551-C-A

Variant names:

• chr21-42347551-C-A
• rs775411596
• NM_005423.5:c.311G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_005423.5(TFF2):​c.311G>T​(p.Arg104Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,614,068 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R104Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TFF2 NM_005423.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.38
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.943

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005423.5. 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
	TFF2	NM_005423.5	MANE Select	c.311G>T	p.Arg104Leu	missense	Exon 3 of 4	NP_005414.1	Q03403

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFF2	ENST00000291526.5	TSL:1 MANE Select	c.311G>T	p.Arg104Leu	missense	Exon 3 of 4	ENSP00000291526.4	Q03403
	TFF2	ENST00000463771.5	TSL:5	n.314G>T		non_coding_transcript_exon	Exon 3 of 4
	TFF2	ENST00000475297.1	TSL:3	n.441G>T		non_coding_transcript_exon	Exon 4 of 5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461880 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727242

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60394

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74348

African (AFR) AF: 0.00 AC: 0 AN: 41444

American (AMR) AF: 0.0000654 AC: 1 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.028	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.061	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Benign	-0.58	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		1.4
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Benign	0.27
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.59
MutPred		0.73		Loss of disorder (P = 0.0411)
MVP		0.68
MPC		1.2
ClinPred		0.93	D
GERP RS		4.0
Varity_R		0.21
gMVP		0.71
Mutation Taster		=78/22	polymorphism

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

Other links and lift over

dbSNP: rs775411596; hg19: chr21-43767660;