rs142025489

chr11-64223393-C-Gchr11-64223393-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.93

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.822

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FERMT3	NM_031471.6	c.1893C>G	p.Ile631Met	missense_variant	15/15	ENST00000345728.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FERMT3	ENST00000345728.10	c.1893C>G	p.Ile631Met	missense_variant	15/15	1	NM_031471.6	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251204 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135824

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.17
Cadd	Benign	0.051
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.82	D;.;T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.26	N
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.82	D;D;D
MetaSVM	Uncertain	0.29	D
MutationAssessor	Uncertain	2.8	M;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.8	D;D;D
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.80
MutPred		0.72		Gain of catalytic residue at V631 (P = 0.1926);.;.;
MVP		0.73
MPC		2.0
ClinPred		0.97	D
GERP RS		-8.5
Varity_R		0.77
gMVP		0.84

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

LitVar

Other links and lift over

dbSNP: rs142025489; hg19: chr11-63990865;