chr11-64220441-G-A

Variant names:

• chr11-64220441-G-A
• rs72920390
• NM_031471.6:c.1317G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_031471.6(FERMT3):​c.1317G>A​(p.Gln439Gln) 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:4
• Conservation: PhyloP100: 1.29
• Publications: 2 publications found

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]

FERMT3 Gene-Disease associations (from GenCC):

• leukocyte adhesion deficiency 3

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, ClinGen

ACMG classification

Our verdict: Benign. The variant received -21 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 Benign/Likely_benign. ClinVar VariationId is 522223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031471.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FERMT3	NM_031471.6	MANE Select	c.1317G>A	p.Gln439Gln	synonymous	Exon 12 of 15	NP_113659.3
	FERMT3	NM_001382362.1		c.1329G>A	p.Gln443Gln	synonymous	Exon 12 of 15	NP_001369291.1
	FERMT3	NM_178443.3		c.1329G>A	p.Gln443Gln	synonymous	Exon 12 of 15	NP_848537.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FERMT3	ENST00000345728.10	TSL:1 MANE Select	c.1317G>A	p.Gln439Gln	synonymous	Exon 12 of 15	ENSP00000339950.5
	FERMT3	ENST00000279227.10	TSL:1	c.1329G>A	p.Gln443Gln	synonymous	Exon 12 of 15	ENSP00000279227.5
	FERMT3	ENST00000698865.1		c.1338G>A	p.Gln446Gln	synonymous	Exon 12 of 15	ENSP00000513992.1

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

GnomAD2 exomes AF: 0.00193 AC: 468 AN: 243076 AF XY: 0.00205

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 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

African (AFR) AF: 0.000179 AC: 6 AN: 33446

American (AMR) AF: 0.000741 AC: 33 AN: 44526

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26100

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39688

South Asian (SAS) AF: 0.00175 AC: 151 AN: 86228

European-Finnish (FIN) AF: 0.00371 AC: 190 AN: 51244

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.00285 AC: 3170 AN: 1111484

Other (OTH) AF: 0.00177 AC: 107 AN: 60322

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

African (AFR) AF: 0.000601 AC: 25 AN: 41576

American (AMR) AF: 0.000653 AC: 10 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4834

European-Finnish (FIN) AF: 0.00245 AC: 26 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00288 AC: 196 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00176 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

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Leukocyte adhesion deficiency 3 (3)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
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
PhyloP100		1.3
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
PromoterAI		-0.010	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs72920390; hg19: chr11-63987913; COSMIC: COSV54177839; COSMIC: COSV54177839;