11-64219313-G-T

Position:

• chr11-64219313-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_031471.6(FERMT3):​c.849G>T​(p.Glu283Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000549 in 1,457,096 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: FERMT3 NM_031471.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.51

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18610609).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FERMT3	NM_031471.6	c.849G>T	p.Glu283Asp	missense_variant	7/15	ENST00000345728.10	NP_113659.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FERMT3	ENST00000345728.10	c.849G>T	p.Glu283Asp	missense_variant	7/15	1	NM_031471.6	ENSP00000339950.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000549 AC: 8 AN: 1457096 Hom.: 0 Cov.: 36 AF XY: 0.00000690 AC XY: 5 AN XY: 724624

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000721

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000413 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Leukocyte adhesion deficiency 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 23, 2022

This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 283 of the FERMT3 protein (p.Glu283Asp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FERMT3-related conditions. ClinVar contains an entry for this variant (Variation ID: 567337). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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	0.27
BayesDel_addAF	Benign	-0.066	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T;T;.
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.89
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.4	.;L;L
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.7	N;N;N
REVEL	Benign	0.19
Sift	Benign	0.12	T;T;T
Sift4G	Benign	0.14	T;T;T
Polyphen		0.054, 0.010	.;B;B
Vest4		0.17, 0.19
MutPred		0.69		Loss of catalytic residue at E283 (P = 0.1261);Loss of catalytic residue at E283 (P = 0.1261);Loss of catalytic residue at E283 (P = 0.1261);
MVP		0.41
MPC		0.63
ClinPred		0.11	T
GERP RS		0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.23
gMVP		0.28

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: rs568602034; hg19: chr11-63986785;