rs72920390

chr11-64220441-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS1

The NM_031471.6(FERMT3):c.1317G>A(p.Gln439=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00243 in 1,611,142 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0025 (6 hom.)
• Consequence: FERMT3 NM_031471.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.29

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006200701).
• BP6: Variant 11-64220441-G-A is Benign according to our data. Variant chr11-64220441-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 522223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64220441-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.29 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00171 (260/152338) while in subpopulation NFE AF= 0.00288 (196/68010). AF 95% confidence interval is 0.00255. There are 0 homozygotes in gnomad4. There are 115 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FERMT3	NM_031471.6	c.1317G>A	p.Gln439=	synonymous_variant	12/15	ENST00000345728.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FERMT3	ENST00000345728.10	c.1317G>A	p.Gln439=	synonymous_variant	12/15	1	NM_031471.6	P4

Frequencies

GnomAD3 genomes AF: 0.00171 AC: 260 AN: 152220 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00245

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00288

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00193 AC: 468 AN: 243076 Hom.: 0 AF XY: 0.00205 AC XY: 272 AN XY: 132602

Gnomad AFR exome AF: 0.000526

Gnomad AMR exome AF: 0.000673

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.0000559

Gnomad SAS exome AF: 0.00197

Gnomad FIN exome AF: 0.00347

Gnomad NFE exome AF: 0.00274

Gnomad OTH exome AF: 0.000841

GnomAD4 exome AF: 0.00251 AC: 3660 AN: 1458804 Hom.: 6 Cov.: 33 AF XY: 0.00256 AC XY: 1860 AN XY: 725834

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000741

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00175

Gnomad4 FIN exome AF: 0.00371

Gnomad4 NFE exome AF: 0.00285

Gnomad4 OTH exome AF: 0.00177

GnomAD4 genome AF: 0.00171 AC: 260 AN: 152338 Hom.: 0 Cov.: 33 AF XY: 0.00154 AC XY: 115 AN XY: 74478

Gnomad4 AFR AF: 0.000601

Gnomad4 AMR AF: 0.000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00245

Gnomad4 NFE AF: 0.00288

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00204 Hom.: 0

Bravo AF: 0.00148

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000683 AC: 3

ESP6500EA AF: 0.00210 AC: 18

ExAC AF: 0.00201 AC: 244

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Leukocyte adhesion deficiency 3 Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Sep 06, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Oct 31, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.12
Cadd	Benign	9.6
Dann	Uncertain	0.98
DEOGEN2	Benign	0.0077	T
Eigen	Benign	0.029
Eigen_PC	Benign	0.022
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.24	T
MetaRNN	Benign	0.0062	T
MetaSVM	Benign	-0.76	T
MutationTaster	Benign	1.0	D;D
PROVEAN	Benign	0.53	N
REVEL	Benign	0.023
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
MVP		0.52
ClinPred		0.035	T
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs72920390; hg19: chr11-63987913; COSMIC: COSV54177839; COSMIC: COSV54177839;