chr11-64211367-C-T

Position:

chr11-64211367-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The NM_031471.6(FERMT3):c.607C>T(p.Pro203Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000142 in 1,610,400 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00080 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000073 ( 0 hom. )

Consequence

FERMT3
NM_031471.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 0.928

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0062835515).

BP6

Variant 11-64211367-C-T is Benign according to our data. Variant chr11-64211367-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 537727.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000802 (122/152182) while in subpopulation AFR AF= 0.00258 (107/41514). AF 95% confidence interval is 0.00218. There are 0 homozygotes in gnomad4. There are 61 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FERMT3	NM_031471.6 link	c.607C>T	p.Pro203Ser	missense_variant	5/15	ENST00000345728.10	NP_113659.3	Q86UX7-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FERMT3	ENST00000345728.10 link	c.607C>T	p.Pro203Ser	missense_variant	5/15	1	NM_031471.6	ENSP00000339950.5		Q86UX7-2

Frequencies

GnomAD3 genomes

AF:

0.000802

AC:

122

AN:

152064

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00259

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000917

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000167

AC:

AN:

239746

Hom.:

AF XY:

0.000107

AC XY:

AN XY:

131008

show subpopulations

Gnomad AFR exome

AF:

0.00243

Gnomad AMR exome

AF:

0.000118

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000734

AC:

107

AN:

1458218

Hom.:

Cov.:

AF XY:

0.0000744

AC XY:

AN XY:

725366

show subpopulations

Gnomad4 AFR exome

AF:

0.00248

Gnomad4 AMR exome

AF:

0.000270

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000802

AC:

122

AN:

152182

Hom.:

Cov.:

AF XY:

0.000820

AC XY:

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.00258

Gnomad4 AMR

AF:

0.000916

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000958

Hom.:

Bravo

AF:

0.000967

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000264

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 19, 2023

The c.607C>T (p.P203S) alteration is located in exon 5 (coding exon 4) of the FERMT3 gene. This alteration results from a C to T substitution at nucleotide position 607, causing the proline (P) at amino acid position 203 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Leukocyte adhesion deficiency 3

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 12, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.063

T;T;.;T

Eigen

Benign

0.065

Eigen_PC

Benign

-0.0076

FATHMM_MKL

Benign

0.58

LIST_S2

Uncertain

0.87

D;T;T;D

M_CAP

Benign

0.055

MetaRNN

Benign

0.0063

T;T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.6

.;L;L;.

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-2.6

D;N;N;D

REVEL

Benign

0.11

Sift

Benign

0.082

T;T;T;D

Sift4G

Benign

0.12

T;T;T;D

Polyphen

0.78, 0.94

.;P;P;.

Vest4

0.40, 0.40

MVP

0.64

MPC

0.50

ClinPred

0.051

GERP RS

2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

3.2

Varity_R

0.085

gMVP

0.48

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over