dbSNP rs1427546535: FERMT2:p.Tyr526Phe (chr14-52864426-T-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_006832.3(FERMT2):c.1577A>T(p.Tyr526Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,182 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Y526C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

FERMT2
NM_006832.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.95

Publications

0 publications found

Variant links:

Genes affected

FERMT2 (HGNC:15767): (FERM domain containing kindlin 2) Enables several functions, including actin binding activity; phosphatidylinositol-3,4,5-trisphosphate binding activity; and type I transforming growth factor beta receptor binding activity. Involved in several processes, including cell surface receptor signaling pathway; positive regulation of cell differentiation; and positive regulation of cellular component biogenesis. Acts upstream of or within cell adhesion and protein localization to cell junction. Located in cytosol; focal adhesion; and nucleoplasm. Is extrinsic component of cytoplasmic side of plasma membrane. Part of adherens junction and plasma membrane. Biomarker of acute myeloid leukemia. [provided by Alliance of Genome Resources, Apr 2022]

FERMT2 links:

ENSG00000285664 (HGNC:):

ENSG00000285664 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FERMT2	NM_006832.3 link	c.1577A>T	p.Tyr526Phe	missense_variant	Exon 12 of 15	ENST00000341590.8	NP_006823.1	Q96AC1-1A0A024R687

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FERMT2	ENST00000341590.8 link	c.1577A>T	p.Tyr526Phe	missense_variant	Exon 12 of 15	1	NM_006832.3	ENSP00000340391.3		Q96AC1-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461182

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726992

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33458

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111360

Other (OTH)

AF:

0.00

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.675

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Uncertain

0.075

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.31

T;T;.;.;.;.

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

.;D;D;D;.;D

M_CAP

Benign

0.038

MetaRNN

Uncertain

0.44

T;T;T;T;T;T

MetaSVM

Uncertain

-0.20

MutationAssessor

Benign

1.6

L;L;.;L;L;L

PhyloP100

8.0

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-0.89

N;N;N;N;N;N

REVEL

Benign

0.27

Sift

Benign

0.72

T;T;T;T;T;T

Sift4G

Benign

0.51

T;T;T;T;T;T

Polyphen

0.99

D;D;.;.;.;B

Vest4

0.54

MutPred

0.37

Gain of catalytic residue at L521 (P = 0);Gain of catalytic residue at L521 (P = 0);.;Gain of catalytic residue at L521 (P = 0);Gain of catalytic residue at L521 (P = 0);Gain of catalytic residue at L521 (P = 0);

MVP

0.66

MPC

1.2

ClinPred

0.89

GERP RS

5.9

PromoterAI

-0.015

Neutral

(source)

Varity_R

0.17

gMVP

0.37

Mutation Taster

=46/54

disease causing

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over