Genetic Variant FERMT3:p.Ile631Met (chr11-64223393-C-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_031471.6(FERMT3):c.1893C>G(p.Ile631Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. I631I) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Consequence

FERMT3
NM_031471.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.93

Publications

3 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.822

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031471.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FERMT3	NM_031471.6	MANE Select	c.1893C>G	p.Ile631Met	missense	Exon 15 of 15	NP_113659.3
FERMT3	NM_001382362.1		c.1905C>G	p.Ile635Met	missense	Exon 15 of 15	NP_001369291.1
FERMT3	NM_178443.3		c.1905C>G	p.Ile635Met	missense	Exon 15 of 15	NP_848537.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FERMT3	ENST00000345728.10	TSL:1 MANE Select	c.1893C>G	p.Ile631Met	missense	Exon 15 of 15	ENSP00000339950.5
FERMT3	ENST00000279227.10	TSL:1	c.1905C>G	p.Ile635Met	missense	Exon 15 of 15	ENSP00000279227.5
FERMT3	ENST00000698865.1		c.1914C>G	p.Ile638Met	missense	Exon 15 of 15	ENSP00000513992.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251204

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.17

CADD

Benign

0.051

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.82

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.26

LIST_S2

Pathogenic

0.99

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.82

MetaSVM

Uncertain

0.29

MutationAssessor

Uncertain

2.8

PhyloP100

-2.9

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-2.8

REVEL

Uncertain

0.60

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.80

MutPred

0.72

Gain of catalytic residue at V631 (P = 0.1926)

MVP

0.73

MPC

2.0

ClinPred

0.97

GERP RS

-8.5

Varity_R

0.77

gMVP

0.84

Mutation Taster

=33/67

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over