rs748770309

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4BS1_Supporting

The NM_031471.6(FERMT3):c.922G>A(p.Gly308Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000372 in 1,610,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

FERMT3
NM_031471.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 1.55

Publications

6 publications found

Variant links:

Genes affected

FERMT3 (HGNC:23151): (FERM domain containing kindlin 3) Kindlins are a small family of proteins that mediate protein-protein interactions involved in integrin activation and thereby have a role in cell adhesion, migration, differentiation, and proliferation. The protein encoded by this gene has a key role in the regulation of hemostasis and thrombosis. This protein may also help maintain the membrane skeleton of erythrocytes. Mutations in this gene cause the autosomal recessive leukocyte adhesion deficiency syndrome-III (LAD-III). Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jan 2010]

FERMT3 Gene-Disease associations (from GenCC):

leukocyte adhesion deficiency 3
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, ClinGen

FERMT3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.3746721).

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000112 (17/152186) while in subpopulation AMR AF = 0.000393 (6/15284). AF 95% confidence interval is 0.00017. There are 0 homozygotes in GnomAd4. There are 13 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FERMT3	NM_031471.6 link	c.922G>A	p.Gly308Arg	missense_variant	Exon 8 of 15	ENST00000345728.10	NP_113659.3	Q86UX7-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FERMT3	ENST00000345728.10 link	c.922G>A	p.Gly308Arg	missense_variant	Exon 8 of 15	1	NM_031471.6	ENSP00000339950.5		Q86UX7-2

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

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:

0.0000441

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000328

AC:

AN:

244096

AF XY:

0.0000151

show subpopulations

Gnomad AFR exome

AF:

0.000256

Gnomad AMR exome

AF:

0.0000878

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000907

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000295

AC:

AN:

1458786

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

725528

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33470

American (AMR)

AF:

0.000112

AC:

AN:

44462

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26080

East Asian (EAS)

AF:

0.00

AC:

AN:

39662

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86154

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51464

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000288

AC:

AN:

1111406

Other (OTH)

AF:

0.00

AC:

AN:

60324

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000112

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.000169

AC:

AN:

41444

American (AMR)

AF:

0.000393

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68032

Other (OTH)

AF:

0.000478

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000155

Hom.:

Bravo

AF:

0.000128

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Leukocyte adhesion deficiency 3

Pathogenic:1Uncertain:1

Jun 10, 2010

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Sep 19, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 308 of the FERMT3 protein (p.Gly308Arg). This variant is present in population databases (rs748770309, gnomAD 0.03%). This missense change has been observed in individual(s) with leukocyte adhesion deficiency III (LAD-III) (PMID: 20357244). ClinVar contains an entry for this variant (Variation ID: 579563). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt FERMT3 protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on FERMT3 function (PMID: 20357244). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.44

T;.

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.022

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.68

T;T

M_CAP

Benign

0.030

MetaRNN

Benign

0.37

T;T

MetaSVM

Benign

-0.66

MutationAssessor

Benign

0.55

N;N

PhyloP100

1.6

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.80

N;N

REVEL

Uncertain

0.32

Sift

Benign

0.38

T;T

Sift4G

Benign

0.56

T;T

Polyphen

0.25

B;B

Vest4

0.74

MutPred

0.34

Loss of ubiquitination at K303 (P = 0.0342);Loss of ubiquitination at K303 (P = 0.0342);

MVP

0.77

MPC

0.45

ClinPred

0.029

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Varity_R

0.18

gMVP

0.53

Mutation Taster

=29/71

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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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rs748770309

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over