chr11-64207420-G-T

Variant names:

• chr11-64207420-G-T
• rs150500299
• NM_031471.6:c.56G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_031471.6(FERMT3):​c.56G>T​(p.Arg19Leu) 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 benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R19Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FERMT3 NM_031471.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.371
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.114121646).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FERMT3	NM_031471.6	MANE Select	c.56G>T	p.Arg19Leu	missense	Exon 2 of 15	NP_113659.3
	FERMT3	NM_001382362.1		c.56G>T	p.Arg19Leu	missense	Exon 2 of 15	NP_001369291.1
	FERMT3	NM_178443.3		c.56G>T	p.Arg19Leu	missense	Exon 2 of 15	NP_848537.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FERMT3	ENST00000345728.10	TSL:1 MANE Select	c.56G>T	p.Arg19Leu	missense	Exon 2 of 15	ENSP00000339950.5
	FERMT3	ENST00000279227.10	TSL:1	c.56G>T	p.Arg19Leu	missense	Exon 2 of 15	ENSP00000279227.5
	FERMT3	ENST00000698865.1		c.56G>T	p.Arg19Leu	missense	Exon 2 of 15	ENSP00000513992.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Leukocyte adhesion deficiency 3 Uncertain:1

Jul 26, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with FERMT3-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with leucine at codon 19 of the FERMT3 protein (p.Arg19Leu). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and leucine.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.037	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.24	T
M_CAP	Benign	0.0099	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.75	N
PhyloP100		0.37
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.074
Sift	Benign	0.34	T
Sift4G	Benign	0.39	T
Polyphen		0.0060	B
Vest4		0.62
MutPred		0.33		Gain of sheet (P = 0.0827)
MVP		0.42
MPC		0.47
ClinPred		0.21	T
GERP RS		2.6
PromoterAI		-0.0079	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.32
gMVP		0.46
Mutation Taster		=72/28	polymorphism

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

Other links and lift over

dbSNP: rs150500299; hg19: chr11-63974892; COSMIC: COSV54181523; COSMIC: COSV54181523;