Genetic Variant FERMT2:p.Gly536Ser (chr14-52861031-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The ENST00000553373.5(FERMT2):c.1606G>A(p.Gly536Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000734 in 1,361,564 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign 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. G536A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

FERMT2
ENST00000553373.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.96

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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.28910154).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FERMT2	NM_006832.3 link	c.1603-566G>A		intron_variant	Intron 12 of 14	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.1603-566G>A		intron_variant	Intron 12 of 14	1	NM_006832.3	ENSP00000340391.3		Q96AC1-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.34e-7

AC:

AN:

1361564

Hom.:

Cov.:

AF XY:

0.00000149

AC XY:

AN XY:

670438

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

29002

American (AMR)

AF:

0.00

AC:

AN:

27296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24332

East Asian (EAS)

AF:

0.00

AC:

AN:

33774

South Asian (SAS)

AF:

0.00

AC:

AN:

69988

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48940

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5622

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1066120

Other (OTH)

AF:

0.0000177

AC:

AN:

56490

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

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

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.76

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.81

T;T;.;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.29

T;T;T;T

MetaSVM

Benign

-1.1

PhyloP100

6.0

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.58

N;N;N;N

REVEL

Benign

0.10

Sift

Benign

0.78

T;T;T;T

Sift4G

Benign

0.79

T;T;T;T

Polyphen

0.84

.;.;.;P

Vest4

0.32, 0.32, 0.31

MutPred

0.46

.;Gain of catalytic residue at D540 (P = 0.0062);Gain of catalytic residue at D540 (P = 0.0062);Gain of catalytic residue at D540 (P = 0.0062);

MVP

0.40

MPC

0.51

ClinPred

0.96

GERP RS

5.5

gMVP

0.49

Mutation Taster

=71/29

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

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14-52861031-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over