11-64223393-C-T

Position:

• chr11-64223393-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_031471.6(FERMT3):​c.1893C>T​(p.Ile631=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00145 in 1,613,966 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (4 hom.)
• Consequence: FERMT3 NM_031471.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -2.93

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 11-64223393-C-T is Benign according to our data. Variant chr11-64223393-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 194564.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=3}. Variant chr11-64223393-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-2.93 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00105 (160/152354) while in subpopulation AMR AF= 0.00314 (48/15308). AF 95% confidence interval is 0.00243. There are 1 homozygotes in gnomad4. There are 72 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FERMT3	NM_031471.6	c.1893C>T	p.Ile631=	synonymous_variant	15/15	ENST00000345728.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FERMT3	ENST00000345728.10	c.1893C>T	p.Ile631=	synonymous_variant	15/15	1	NM_031471.6	P4

Frequencies

GnomAD3 genomes AF: 0.00105 AC: 160 AN: 152236 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00141

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000943 AC: 237 AN: 251204 Hom.: 0 AF XY: 0.000979 AC XY: 133 AN XY: 135824

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00171

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.00136

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00149 AC: 2176 AN: 1461612 Hom.: 4 Cov.: 33 AF XY: 0.00146 AC XY: 1064 AN XY: 727094

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.00159

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000220

Gnomad4 FIN exome AF: 0.000132

Gnomad4 NFE exome AF: 0.00182

Gnomad4 OTH exome AF: 0.000778

GnomAD4 genome AF: 0.00105 AC: 160 AN: 152354 Hom.: 1 Cov.: 33 AF XY: 0.000966 AC XY: 72 AN XY: 74502

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.00314

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00141

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00131 Hom.: 0

Bravo AF: 0.000929

EpiCase AF: 0.00147

EpiControl AF: 0.00142

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Leukocyte adhesion deficiency 3 Benign:3

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Oct 02, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 12, 2024	- -

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 23, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	FERMT3: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.18
DANN	Benign	0.91

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: rs142025489; hg19: chr11-63990865; COSMIC: COSV99655877; COSMIC: COSV99655877;