11-64211102-GAGAAGA-GAGA

Variant names:

• chr11-64211102-GAGA-G
• rs759155629
• NM_031471.6:c.456_458delGAA

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP3 BS1_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.44
• 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: Likely_benign. The variant received -2 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_031471.6
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 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 GnomAdExome4. There are 109 alleles in the male GnomAdExome4 subpopulation. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FERMT3	NM_031471.6	MANE Select	c.456_458delGAA	p.Lys153del	disruptive_inframe_deletion	Exon 4 of 15	NP_113659.3
	FERMT3	NM_001382362.1		c.456_458delGAA	p.Lys153del	disruptive_inframe_deletion	Exon 4 of 15	NP_001369291.1	Q86UX7-1
	FERMT3	NM_178443.3		c.456_458delGAA	p.Lys153del	disruptive_inframe_deletion	Exon 4 of 15	NP_848537.1	Q86UX7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FERMT3	ENST00000345728.10	TSL:1 MANE Select	c.456_458delGAA	p.Lys153del	disruptive_inframe_deletion	Exon 4 of 15	ENSP00000339950.5	Q86UX7-2
	FERMT3	ENST00000279227.10	TSL:1	c.456_458delGAA	p.Lys153del	disruptive_inframe_deletion	Exon 4 of 15	ENSP00000279227.5	Q86UX7-1
	FERMT3	ENST00000698865.1		c.456_458delGAA	p.Lys153del	disruptive_inframe_deletion	Exon 4 of 15	ENSP00000513992.1	A0A8V8TP41

Frequencies

GnomAD3 genomes AF: 0.0000858 AC: 13 AN: 151528 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.000113 AC: 20 AN: 176786 AF XY: 0.000116

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 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.: 0 AF XY: 0.000155 AC XY: 109 AN XY: 702474

African (AFR) AF: 0.00 AC: 0 AN: 32228

American (AMR) AF: 0.0000259 AC: 1 AN: 38648

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25340

East Asian (EAS) AF: 0.0000810 AC: 3 AN: 37032

South Asian (SAS) AF: 0.0000370 AC: 3 AN: 81178

European-Finnish (FIN) AF: 0.000277 AC: 14 AN: 50620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5704

European-Non Finnish (NFE) AF: 0.000184 AC: 201 AN: 1090032

Other (OTH) AF: 0.000153 AC: 9 AN: 58744

GnomAD4 genome AF: 0.0000858 AC: 13 AN: 151528 Hom.: 0 Cov.: 32 AF XY: 0.000149 AC XY: 11 AN XY: 73948

African (AFR) AF: 0.0000728 AC: 3 AN: 41230

American (AMR) AF: 0.000132 AC: 2 AN: 15162

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5138

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10486

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 67920

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000540 Hom.: 0

Bravo AF: 0.0000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Leukocyte adhesion deficiency 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.4
Mutation Taster		=64/36	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: rs759155629; hg19: chr11-63978574;