dbSNP rs201501349: FERMT3:p.Ala468Ala (chr11-64220528-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_031471.6(FERMT3):c.1404C>T(p.Ala468Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000348 in 1,607,960 control chromosomes in the GnomAD database, including 3 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 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00021 ( 1 hom. )

Consequence

FERMT3
NM_031471.6 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.05

Publications

0 publications found

Variant links:

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

FERMT3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0070388317).

BP6

Variant 11-64220528-C-T is Benign according to our data. Variant chr11-64220528-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 497277.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.05 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00168 (256/152370) while in subpopulation AFR AF = 0.00577 (240/41586). AF 95% confidence interval is 0.00517. There are 2 homozygotes in GnomAd4. There are 121 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FERMT3	NM_031471.6	MANE Select	c.1404C>T	p.Ala468Ala	synonymous	Exon 12 of 15	NP_113659.3
FERMT3	NM_001382362.1		c.1416C>T	p.Ala472Ala	synonymous	Exon 12 of 15	NP_001369291.1	Q86UX7-1
FERMT3	NM_178443.3		c.1416C>T	p.Ala472Ala	synonymous	Exon 12 of 15	NP_848537.1	Q86UX7-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FERMT3	ENST00000345728.10	TSL:1 MANE Select	c.1404C>T	p.Ala468Ala	synonymous	Exon 12 of 15	ENSP00000339950.5	Q86UX7-2
FERMT3	ENST00000279227.10	TSL:1	c.1416C>T	p.Ala472Ala	synonymous	Exon 12 of 15	ENSP00000279227.5	Q86UX7-1
FERMT3	ENST00000698865.1		c.1425C>T	p.Ala475Ala	synonymous	Exon 12 of 15	ENSP00000513992.1	A0A8V8TP41

Frequencies

GnomAD3 genomes

AF:

0.00167

AC:

254

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00574

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000719

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.000499

AC:

116

AN:

232526

AF XY:

0.000439

show subpopulations

Gnomad AFR exome

AF:

0.00713

Gnomad AMR exome

AF:

0.000301

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000193

Gnomad OTH exome

AF:

0.000701

GnomAD4 exome

AF:

0.000208

AC:

303

AN:

1455590

Hom.:

Cov.:

AF XY:

0.000171

AC XY:

124

AN XY:

723882

show subpopulations

African (AFR)

AF:

0.00763

AC:

254

AN:

33296

American (AMR)

AF:

0.000296

AC:

AN:

43894

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25974

East Asian (EAS)

AF:

0.00

AC:

AN:

39362

South Asian (SAS)

AF:

0.0000350

AC:

AN:

85670

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51932

Middle Eastern (MID)

AF:

0.000521

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1109588

Other (OTH)

AF:

0.000432

AC:

AN:

60116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

104

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00168

AC:

256

AN:

152370

Hom.:

Cov.:

AF XY:

0.00162

AC XY:

121

AN XY:

74502

show subpopulations

African (AFR)

AF:

0.00577

AC:

240

AN:

41586

American (AMR)

AF:

0.000718

AC:

AN:

15314

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68034

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000605

Hom.:

Bravo

AF:

0.00221

ESP6500AA

AF:

0.00572

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000555

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Leukocyte adhesion deficiency 3 (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0094

Eigen

Benign

-0.050

Eigen_PC

Benign

-0.034

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.32

MetaRNN

Benign

0.0070

MetaSVM

Benign

-0.74

PhyloP100

2.1

PROVEAN

Benign

-0.99

REVEL

Benign

0.19

Sift

Benign

0.12

Sift4G

Uncertain

0.037

MVP

0.46

ClinPred

0.0081

GERP RS

3.4

PromoterAI

-0.076

Neutral

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over