rs76744324

chr11-64220444-G-A

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.1320G>A(p.Gln440=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00234 in 1,611,164 control chromosomes in the GnomAD database, including 89 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (45 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (44 hom.)
• Consequence: FERMT3 NM_031471.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.55

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=0.005191624).
• BP6: Variant 11-64220444-G-A is Benign according to our data. Variant chr11-64220444-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 470171.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.55 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0128 (1943/152340) while in subpopulation AFR AF= 0.0445 (1850/41564). AF 95% confidence interval is 0.0428. There are 45 homozygotes in gnomad4. There are 935 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 45 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FERMT3	NM_031471.6	c.1320G>A	p.Gln440=	synonymous_variant	12/15	ENST00000345728.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FERMT3	ENST00000345728.10	c.1320G>A	p.Gln440=	synonymous_variant	12/15	1	NM_031471.6	P4

Frequencies

GnomAD3 genomes AF: 0.0128 AC: 1943 AN: 152222 Hom.: 45 Cov.: 33

Gnomad AFR AF: 0.0446

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00425

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.00296 AC: 717 AN: 242546 Hom.: 18 AF XY: 0.00208 AC XY: 276 AN XY: 132386

Gnomad AFR exome AF: 0.0441

Gnomad AMR exome AF: 0.00126

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000275

Gnomad OTH exome AF: 0.000672

GnomAD4 exome AF: 0.00125 AC: 1821 AN: 1458824 Hom.: 44 Cov.: 33 AF XY: 0.00105 AC XY: 761 AN XY: 725814

Gnomad4 AFR exome AF: 0.0471

Gnomad4 AMR exome AF: 0.00173

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000234

Gnomad4 OTH exome AF: 0.00224

GnomAD4 genome AF: 0.0128 AC: 1943 AN: 152340 Hom.: 45 Cov.: 33 AF XY: 0.0126 AC XY: 935 AN XY: 74484

Gnomad4 AFR AF: 0.0445

Gnomad4 AMR AF: 0.00425

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00328 Hom.: 3

Bravo AF: 0.0137

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0398 AC: 175

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.00367 AC: 444

Asia WGS AF: 0.00115 AC: 4 AN: 3478

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	Mar 17, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.14
Cadd	Benign	5.3
Dann	Benign	0.97
DEOGEN2	Benign	0.0076	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.24	T
MetaRNN	Benign	0.0052	T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	D;D
PROVEAN	Benign	0.31	N
REVEL	Benign	0.013
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
MVP		0.55
ClinPred		0.039	T
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs76744324; hg19: chr11-63987916;