Genetic Variant FERMT3:p.Lys153del (chr11-64211102-GAGA-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP3BS1_Supporting

The NM_031471.6(FERMT3):c.456_458delGAA(p.Lys153del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.000155 in 1,571,054 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000086 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

FERMT3
NM_031471.6 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.44

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP3

Nonframeshift variant in repetitive region in NM_031471.6

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000163 (231/1419526) while in subpopulation NFE AF= 0.000184 (201/1090032). AF 95% confidence interval is 0.000164. There are 0 homozygotes in gnomad4_exome. There are 109 alleles in male gnomad4_exome 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 rank	MANE	Protein	UniProt
FERMT3	NM_031471.6 link	c.456_458delGAA	p.Lys153del	disruptive_inframe_deletion	Exon 4 of 15	ENST00000345728.10	NP_113659.3	Q86UX7-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FERMT3	ENST00000345728.10 link	c.456_458delGAA	p.Lys153del	disruptive_inframe_deletion	Exon 4 of 15	1	NM_031471.6	ENSP00000339950.5		Q86UX7-2

Frequencies

GnomAD3 genomes

AF:

0.0000858

AC:

AN:

151528

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000728

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000132

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000113

AC:

AN:

176786

Hom.:

AF XY:

0.000116

AC XY:

AN XY:

94832

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000367

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000151

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000179

Gnomad NFE exome

AF:

0.000196

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000163

AC:

231

AN:

1419526

Hom.:

AF XY:

0.000155

AC XY:

109

AN XY:

702474

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000259

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000810

Gnomad4 SAS exome

AF:

0.0000370

Gnomad4 FIN exome

AF:

0.000277

Gnomad4 NFE exome

AF:

0.000184

Gnomad4 OTH exome

AF:

0.000153

GnomAD4 genome

AF:

0.0000858

AC:

AN:

151528

Hom.:

Cov.:

AF XY:

0.000149

AC XY:

AN XY:

73948

show subpopulations

Gnomad4 AFR

AF:

0.0000728

Gnomad4 AMR

AF:

0.000132

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Leukocyte adhesion deficiency 3

Uncertain:1

Nov 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.456_458del, results in the deletion of 1 amino acid(s) of the FERMT3 protein (p.Lys153del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs759155629, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with FERMT3-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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

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

Below is the list of publications found by LitVar. It may be empty.

11-64211102-GAGAAGA-GAGA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over