rs199508330

Positions:

• chr11-64219559-G-C
• chr11-64219559-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_031471.6(FERMT3):​c.930G>C​(p.Val310=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00162 in 1,611,558 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V310V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (39 hom.)
• Consequence: FERMT3 NM_031471.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.158

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 11-64219559-G-C is Benign according to our data. Variant chr11-64219559-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 537724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64219559-G-C is described in Lovd as [Likely_benign]. Variant chr11-64219559-G-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.158 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00123 (187/152282) while in subpopulation SAS AF= 0.0249 (120/4826). AF 95% confidence interval is 0.0213. There are 1 homozygotes in gnomad4. There are 118 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 39 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FERMT3	NM_031471.6	c.930G>C	p.Val310=	synonymous_variant	8/15	ENST00000345728.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FERMT3	ENST00000345728.10	c.930G>C	p.Val310=	synonymous_variant	8/15	1	NM_031471.6	P4

Frequencies

GnomAD3 genomes AF: 0.00123 AC: 187 AN: 152164 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00847

Gnomad SAS AF: 0.0248

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00367 AC: 900 AN: 245474 Hom.: 14 AF XY: 0.00469 AC XY: 625 AN XY: 133370

Gnomad AFR exome AF: 0.000381

Gnomad AMR exome AF: 0.000146

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00645

Gnomad SAS exome AF: 0.0245

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000992

Gnomad OTH exome AF: 0.00234

GnomAD4 exome AF: 0.00166 AC: 2422 AN: 1459276 Hom.: 39 Cov.: 36 AF XY: 0.00230 AC XY: 1670 AN XY: 725846

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000202

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00310

Gnomad4 SAS exome AF: 0.0240

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000648

Gnomad4 OTH exome AF: 0.00214

GnomAD4 genome AF: 0.00123 AC: 187 AN: 152282 Hom.: 1 Cov.: 33 AF XY: 0.00158 AC XY: 118 AN XY: 74450

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00849

Gnomad4 SAS AF: 0.0249

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000258 Hom.: 0

Bravo AF: 0.000540

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Leukocyte adhesion deficiency 3 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 08, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	4.6
DANN	Benign	0.88
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		3.2

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: rs199508330; hg19: chr11-63987031;