11-64220630-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_031471.6(FERMT3):c.1506C>T(p.Leu502=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.172 in 1,610,504 control chromosomes in the GnomAD database, including 24,901 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2479 hom., cov: 33)
  • Exomes 𝑓: 0.17 (22422 hom.)
• Consequence: FERMT3 NM_031471.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.38

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 (MetaRNN=0.0011279881).
• BP6: Variant 11-64220630-C-T is Benign according to our data. Variant chr11-64220630-C-T is described in ClinVar as [Benign]. Clinvar id is 402864.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64220630-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.38 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.276 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FERMT3	NM_031471.6	c.1506C>T	p.Leu502=	synonymous_variant	12/15	ENST00000345728.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FERMT3	ENST00000345728.10	c.1506C>T	p.Leu502=	synonymous_variant	12/15	1	NM_031471.6	P4

Frequencies

GnomAD3 genomes AF: 0.174 AC: 26416 AN: 152106 Hom.: 2473 Cov.: 33

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.130

Gnomad AMR AF: 0.282

Gnomad ASJ AF: 0.175

Gnomad EAS AF: 0.188

Gnomad SAS AF: 0.0887

Gnomad FIN AF: 0.175

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.173

Gnomad OTH AF: 0.199

GnomAD3 exomes AF: 0.179 AC: 43003 AN: 240268 Hom.: 4273 AF XY: 0.173 AC XY: 22722 AN XY: 131338

Gnomad AFR exome AF: 0.134

Gnomad AMR exome AF: 0.303

Gnomad ASJ exome AF: 0.179

Gnomad EAS exome AF: 0.185

Gnomad SAS exome AF: 0.0974

Gnomad FIN exome AF: 0.169

Gnomad NFE exome AF: 0.169

Gnomad OTH exome AF: 0.189

GnomAD4 exome AF: 0.172 AC: 250099 AN: 1458280 Hom.: 22422 Cov.: 35 AF XY: 0.169 AC XY: 122748 AN XY: 725280

Gnomad4 AFR exome AF: 0.140

Gnomad4 AMR exome AF: 0.307

Gnomad4 ASJ exome AF: 0.178

Gnomad4 EAS exome AF: 0.184

Gnomad4 SAS exome AF: 0.0965

Gnomad4 FIN exome AF: 0.170

Gnomad4 NFE exome AF: 0.172

Gnomad4 OTH exome AF: 0.182

GnomAD4 genome AF: 0.174 AC: 26448 AN: 152224 Hom.: 2479 Cov.: 33 AF XY: 0.175 AC XY: 13044 AN XY: 74424

Gnomad4 AFR AF: 0.142

Gnomad4 AMR AF: 0.283

Gnomad4 ASJ AF: 0.175

Gnomad4 EAS AF: 0.187

Gnomad4 SAS AF: 0.0890

Gnomad4 FIN AF: 0.175

Gnomad4 NFE AF: 0.173

Gnomad4 OTH AF: 0.204

Alfa AF: 0.168 Hom.: 947

Bravo AF: 0.182

TwinsUK AF: 0.172 AC: 639

ALSPAC AF: 0.167 AC: 643

ESP6500AA AF: 0.137 AC: 601

ESP6500EA AF: 0.170 AC: 1457

ExAC AF: 0.167 AC: 20227

Asia WGS AF: 0.156 AC: 541 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Leukocyte adhesion deficiency 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	0.94
Dann	Benign	0.90
DEOGEN2	Benign	0.018	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.37	T
MetaRNN	Benign	0.0011	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	4.7e-13	P;P
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.0090
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.055	T
ClinPred		0.010	T
GERP RS		-8.4

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: rs3802933; hg19: chr11-63988102; COSMIC: COSV54180771; COSMIC: COSV54180771;