Genetic Variant FERMT2:p.Ile574Val (chr14-52860348-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006832.3(FERMT2):c.1720A>G(p.Ile574Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,504 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I574S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

FERMT2
NM_006832.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.00

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.18049085).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FERMT2	NM_006832.3 link	c.1720A>G	p.Ile574Val	missense_variant	Exon 13 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.1720A>G	p.Ile574Val	missense_variant	Exon 13 of 15	1	NM_006832.3	ENSP00000340391.3		Q96AC1-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461504

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727048

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33462

American (AMR)

AF:

0.00

AC:

AN:

44644

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.000101

AC:

AN:

39672

South Asian (SAS)

AF:

0.00

AC:

AN:

86196

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53386

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111882

Other (OTH)

AF:

0.00

AC:

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 20, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1741A>G (p.I581V) alteration is located in exon 14 (coding exon 13) of the FERMT2 gene. This alteration results from a A to G substitution at nucleotide position 1741, causing the isoleucine (I) at amino acid position 581 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.070

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.20

T;T;.;.;.;.

Eigen

Benign

-0.22

Eigen_PC

Benign

0.043

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.88

.;D;D;D;.;D

M_CAP

Benign

0.010

MetaRNN

Benign

0.18

T;T;T;T;T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

0.84

L;L;.;.;.;.

PhyloP100

3.0

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.090

N;N;N;N;N;N

REVEL

Benign

0.25

Sift

Benign

0.90

T;T;T;T;T;T

Sift4G

Benign

1.0

T;T;T;T;T;T

Polyphen

0.017

B;B;.;.;.;B

Vest4

0.21

MutPred

0.34

Gain of catalytic residue at I570 (P = 0.0072);Gain of catalytic residue at I570 (P = 0.0072);.;.;.;.;

MVP

0.42

MPC

0.33

ClinPred

0.85

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.065

gMVP

0.38

Mutation Taster

=95/5

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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14-52860348-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over