chr11-64207494-G-A

Variant names:

• chr11-64207494-G-A
• rs149000560
• NM_031471.6:c.130G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP3 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_031471.6(FERMT3):​c.130G>A​(p.Gly44Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00766 in 1,613,364 control chromosomes in the GnomAD database, including 86 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0057 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0079 (80 hom.)
• Consequence: FERMT3 NM_031471.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 9.32
• Publications: 16 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: Benign. The variant received -19 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 10: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, FATHMM_MKL, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when max_spliceai, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.011366427).
• BP6: Variant 11-64207494-G-A is Benign according to our data. Variant chr11-64207494-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 195388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00566 (862/152236) while in subpopulation NFE AF = 0.00832 (566/68012). AF 95% confidence interval is 0.00775. There are 6 homozygotes in GnomAd4. There are 397 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

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.130G>A	p.Gly44Arg	missense	Exon 2 of 15	NP_113659.3
	FERMT3	NM_001382362.1		c.130G>A	p.Gly44Arg	missense	Exon 2 of 15	NP_001369291.1	Q86UX7-1
	FERMT3	NM_178443.3		c.130G>A	p.Gly44Arg	missense	Exon 2 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.130G>A	p.Gly44Arg	missense	Exon 2 of 15	ENSP00000339950.5	Q86UX7-2
	FERMT3	ENST00000279227.10	TSL:1	c.130G>A	p.Gly44Arg	missense	Exon 2 of 15	ENSP00000279227.5	Q86UX7-1
	FERMT3	ENST00000698865.1		c.130G>A	p.Gly44Arg	missense	Exon 2 of 15	ENSP00000513992.1	A0A8V8TP41

Frequencies

GnomAD3 genomes AF: 0.00567 AC: 863 AN: 152118 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00142

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.00543

Gnomad ASJ AF: 0.0268

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.00832

Gnomad OTH AF: 0.00718

GnomAD2 exomes AF: 0.00600 AC: 1501 AN: 250244 AF XY: 0.00607

Gnomad AFR exome AF: 0.00167

Gnomad AMR exome AF: 0.00385

Gnomad ASJ exome AF: 0.0272

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00144

Gnomad NFE exome AF: 0.00807

Gnomad OTH exome AF: 0.00967

GnomAD4 exome AF: 0.00787 AC: 11493 AN: 1461128 Hom.: 80 Cov.: 31 AF XY: 0.00773 AC XY: 5619 AN XY: 726852

African (AFR) AF: 0.00173 AC: 58 AN: 33476

American (AMR) AF: 0.00392 AC: 175 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.0287 AC: 749 AN: 26070

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00183 AC: 158 AN: 86186

European-Finnish (FIN) AF: 0.00188 AC: 100 AN: 53308

Middle Eastern (MID) AF: 0.0458 AC: 263 AN: 5744

European-Non Finnish (NFE) AF: 0.00853 AC: 9480 AN: 1111596

Other (OTH) AF: 0.00845 AC: 510 AN: 60372

GnomAD4 genome AF: 0.00566 AC: 862 AN: 152236 Hom.: 6 Cov.: 33 AF XY: 0.00533 AC XY: 397 AN XY: 74422

African (AFR) AF: 0.00142 AC: 59 AN: 41548

American (AMR) AF: 0.00543 AC: 83 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0268 AC: 93 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10606

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.00832 AC: 566 AN: 68012

Other (OTH) AF: 0.00710 AC: 15 AN: 2112

Alfa AF: 0.00828 Hom.: 25

Bravo AF: 0.00625

TwinsUK AF: 0.00809 AC: 30

ALSPAC AF: 0.00727 AC: 28

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00966 AC: 83

ExAC AF: 0.00568 AC: 689

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00943

EpiControl AF: 0.00795

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Leukocyte adhesion deficiency 3 (2)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Uncertain	0.014	T
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.14	T
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.30	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		9.3
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-6.1	D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.90		Gain of MoRF binding (P = 0.0028)
MVP		0.79
MPC		1.3
ClinPred		0.019	T
GERP RS		4.5
PromoterAI		-0.0037	Neutral
Varity_R		0.87
gMVP		0.79
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs149000560; hg19: chr11-63974966; COSMIC: COSV99043647; COSMIC: COSV99043647;