rs145419469

chr11-64210782-G-Achr11-64210782-G-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BS1_Supporting

The NM_031471.6(FERMT3):c.332G>A(p.Arg111His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000954 in 1,613,992 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts 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. R111C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00063 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00099 (1 hom.)
• Consequence: FERMT3 NM_031471.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 1.86

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.069322914).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00063 (96/152332) while in subpopulation NFE AF= 0.00104 (71/68028). AF 95% confidence interval is 0.000848. There are 0 homozygotes in gnomad4. There are 38 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FERMT3	NM_031471.6	c.332G>A	p.Arg111His	missense_variant	3/15	ENST00000345728.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FERMT3	ENST00000345728.10	c.332G>A	p.Arg111His	missense_variant	3/15	1	NM_031471.6	P4

Frequencies

GnomAD3 genomes AF: 0.000631 AC: 96 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00104

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000598 AC: 150 AN: 250722 Hom.: 0 AF XY: 0.000641 AC XY: 87 AN XY: 135646

Gnomad AFR exome AF: 0.000310

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.0000546

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00108

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000987 AC: 1443 AN: 1461660 Hom.: 1 Cov.: 35 AF XY: 0.000967 AC XY: 703 AN XY: 727162

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000359

Gnomad4 FIN exome AF: 0.0000751

Gnomad4 NFE exome AF: 0.00122

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.000630 AC: 96 AN: 152332 Hom.: 0 Cov.: 32 AF XY: 0.000510 AC XY: 38 AN XY: 74486

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00104

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00113 Hom.: 0

Bravo AF: 0.000616

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000682 AC: 3

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000527 AC: 64

EpiCase AF: 0.000709

EpiControl AF: 0.000889

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Leukocyte adhesion deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetics and Molecular Pathology, SA Pathology

Mar 15, 2021

- -

Leukocyte adhesion deficiency 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 111 of the FERMT3 protein (p.Arg111His). This variant is present in population databases (rs145419469, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. 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: 578258). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FERMT3 protein function. 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	0.11
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.51
Cadd	Uncertain	24
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.046	T;T;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.86	D;D;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.069	T;T;T
MetaSVM	Benign	-0.84	T
MutationTaster	Benign	0.69	D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.8	N;N;N
REVEL	Benign	0.052
Sift	Benign	0.055	T;T;T
Sift4G	Benign	0.085	T;T;T
Polyphen		0.83, 1.0	.;P;D
Vest4		0.36, 0.40
MVP		0.39
MPC		0.74
ClinPred		0.032	T
GERP RS		3.7
Varity_R		0.076
gMVP		0.33

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: rs145419469; hg19: chr11-63978254;