11-64207523-C-G

Variant names:

• chr11-64207523-C-G
• rs142815441
• NM_031471.6:c.159C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_031471.6(FERMT3):​c.159C>G​(p.Ile53Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00311 in 1,602,188 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0032 (10 hom.)
• Consequence: FERMT3 NM_031471.6 missense, splice_region
• Scores: Splicing: ADA: 0.1283
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.241
• Publications: 7 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), Orphanet, Genomics England PanelApp, ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0050028563).
• BP6: Variant 11-64207523-C-G is Benign according to our data. Variant chr11-64207523-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 195387.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 = 0.00225 (343/152240) while in subpopulation NFE AF = 0.00404 (275/68006). AF 95% confidence interval is 0.00365. There are 1 homozygotes in GnomAd4. There are 147 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 10 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.159C>G	p.Ile53Met	missense splice_region	Exon 2 of 15	NP_113659.3
	FERMT3	NM_001382362.1		c.159C>G	p.Ile53Met	missense splice_region	Exon 2 of 15	NP_001369291.1	Q86UX7-1
	FERMT3	NM_178443.3		c.159C>G	p.Ile53Met	missense splice_region	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.159C>G	p.Ile53Met	missense splice_region	Exon 2 of 15	ENSP00000339950.5	Q86UX7-2
	FERMT3	ENST00000279227.10	TSL:1	c.159C>G	p.Ile53Met	missense splice_region	Exon 2 of 15	ENSP00000279227.5	Q86UX7-1
	FERMT3	ENST00000698865.1		c.159C>G	p.Ile53Met	missense splice_region	Exon 2 of 15	ENSP00000513992.1	A0A8V8TP41

Frequencies

GnomAD3 genomes AF: 0.00225 AC: 343 AN: 152122 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00404

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00193 AC: 472 AN: 244656 AF XY: 0.00210

Gnomad AFR exome AF: 0.000619

Gnomad AMR exome AF: 0.000849

Gnomad ASJ exome AF: 0.000852

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00113

Gnomad NFE exome AF: 0.00346

Gnomad OTH exome AF: 0.00301

GnomAD4 exome AF: 0.00320 AC: 4647 AN: 1449948 Hom.: 10 Cov.: 31 AF XY: 0.00309 AC XY: 2226 AN XY: 719430

African (AFR) AF: 0.000330 AC: 11 AN: 33322

American (AMR) AF: 0.00111 AC: 49 AN: 44312

Ashkenazi Jewish (ASJ) AF: 0.000744 AC: 19 AN: 25552

East Asian (EAS) AF: 0.00 AC: 0 AN: 39440

South Asian (SAS) AF: 0.000140 AC: 12 AN: 85424

European-Finnish (FIN) AF: 0.00115 AC: 61 AN: 52928

Middle Eastern (MID) AF: 0.000366 AC: 2 AN: 5458

European-Non Finnish (NFE) AF: 0.00393 AC: 4342 AN: 1103684

Other (OTH) AF: 0.00252 AC: 151 AN: 59828

GnomAD4 genome AF: 0.00225 AC: 343 AN: 152240 Hom.: 1 Cov.: 33 AF XY: 0.00198 AC XY: 147 AN XY: 74424

African (AFR) AF: 0.000481 AC: 20 AN: 41554

American (AMR) AF: 0.00229 AC: 35 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00404 AC: 275 AN: 68006

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00329 Hom.: 0

Bravo AF: 0.00227

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000909 AC: 4

ESP6500EA AF: 0.00535 AC: 46

ExAC AF: 0.00185 AC: 225

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	FERMT3-related disorder (1)
-	-	1	Leukocyte adhesion deficiency 3 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	16
DANN	Benign	0.91
DEOGEN2	Benign	0.020	T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.0050	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.24
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.058
Sift	Benign	0.15	T
Sift4G	Benign	0.079	T
Polyphen		0.031	B
Vest4		0.26
MVP		0.65
MPC		0.39
ClinPred		0.013	T
GERP RS		4.5
PromoterAI		-0.068	Neutral
Varity_R		0.13
gMVP		0.35
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.13
dbscSNV1_RF	Benign	0.24
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: rs142815441; hg19: chr11-63974995;