rs149000560

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP3BP4_StrongBP6_Very_StrongBS1BS2

The NM_031471.6(FERMT3):c.130G>A(p.Gly44Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00766 in 1,613,364 control chromosomes in the GnomAD database, including 86 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0057 ( 6 hom., cov: 33)

Exomes 𝑓: 0.0079 ( 80 hom. )

Consequence

FERMT3
NM_031471.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 9.32

Publications

16 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: Benign. The variant received -19 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 10: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, FATHMM_MKL, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when max_spliceai, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.011366427).

BP6

Variant 11-64207494-G-A is Benign according to our data. Variant chr11-64207494-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 195388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00566 (862/152236) while in subpopulation NFE AF = 0.00832 (566/68012). AF 95% confidence interval is 0.00775. There are 6 homozygotes in GnomAd4. There are 397 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FERMT3	NM_031471.6 link	c.130G>A	p.Gly44Arg	missense_variant	Exon 2 of 15	ENST00000345728.10	NP_113659.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FERMT3	ENST00000345728.10 link	c.130G>A	p.Gly44Arg	missense_variant	Exon 2 of 15	1	NM_031471.6	ENSP00000339950.5

Frequencies

GnomAD3 genomes

AF:

0.00567

AC:

863

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00142

Gnomad AMI

AF:

0.0252

Gnomad AMR

AF:

0.00543

Gnomad ASJ

AF:

0.0268

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.0538

Gnomad NFE

AF:

0.00832

Gnomad OTH

AF:

0.00718

GnomAD2 exomes

AF:

0.00600

AC:

1501

AN:

250244

AF XY:

0.00607

show subpopulations

Gnomad AFR exome

AF:

0.00167

Gnomad AMR exome

AF:

0.00385

Gnomad ASJ exome

AF:

0.0272

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00144

Gnomad NFE exome

AF:

0.00807

Gnomad OTH exome

AF:

0.00967

GnomAD4 exome

AF:

0.00787

AC:

11493

AN:

1461128

Hom.:

Cov.:

AF XY:

0.00773

AC XY:

5619

AN XY:

726852

show subpopulations

African (AFR)

AF:

0.00173

AC:

AN:

33476

American (AMR)

AF:

0.00392

AC:

175

AN:

44688

Ashkenazi Jewish (ASJ)

AF:

0.0287

AC:

749

AN:

26070

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.00183

AC:

158

AN:

86186

European-Finnish (FIN)

AF:

0.00188

AC:

100

AN:

53308

Middle Eastern (MID)

AF:

0.0458

AC:

263

AN:

5744

European-Non Finnish (NFE)

AF:

0.00853

AC:

9480

AN:

1111596

Other (OTH)

AF:

0.00845

AC:

510

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

676

1351

2027

2702

3378

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

368

736

1104

1472

1840

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00566

AC:

862

AN:

152236

Hom.:

Cov.:

AF XY:

0.00533

AC XY:

397

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.00142

AC:

AN:

41548

American (AMR)

AF:

0.00543

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0268

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.000414

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000471

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00832

AC:

566

AN:

68012

Other (OTH)

AF:

0.00710

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

135

180

225

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00828

Hom.:

Bravo

AF:

0.00625

TwinsUK

AF:

0.00809

AC:

ALSPAC

AF:

0.00727

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.00966

AC:

ExAC

AF:

0.00568

AC:

689

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00943

EpiControl

AF:

0.00795

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

May 28, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Leukocyte adhesion deficiency 3

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Jun 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

FERMT3: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Uncertain

0.014

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.14

T;D;.

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;D

MetaRNN

Benign

0.011

T;T;T

MetaSVM

Benign

-0.30

MutationAssessor

Uncertain

2.5

.;M;M

PhyloP100

9.3

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-6.1

D;D;D

REVEL

Pathogenic

0.70

Sift

Uncertain

0.0010

D;D;D

Sift4G

Uncertain

0.0040

D;D;D

Polyphen

1.0, 1.0

.;D;D

Vest4

0.87, 0.89

MutPred

0.90

Gain of MoRF binding (P = 0.0028);Gain of MoRF binding (P = 0.0028);Gain of MoRF binding (P = 0.0028);

MVP

0.79

MPC

1.3

ClinPred

0.019

GERP RS

4.5

PromoterAI

-0.0037

Neutral

(source)

Varity_R

0.87

gMVP

0.79

Mutation Taster

=88/12

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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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