rs146180696

Positions:

chr20-6097571-C-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_017671.5(FERMT1):c.910G>T(p.Glu304*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000125 in 1,613,976 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

FERMT1
NM_017671.5 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3O:1

Conservation

PhyloP100: 5.03

Variant links:

Genes affected

FERMT1 (HGNC:15889): (FERM domain containing kindlin 1) This gene encodes a member of the fermitin family, and contains a FERM domain and a pleckstrin homology domain. The encoded protein is involved in integrin signaling and linkage of the actin cytoskeleton to the extracellular matrix. Mutations in this gene have been linked to Kindler syndrome. [provided by RefSeq, Dec 2009]

FERMT1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 20-6097571-C-A is Pathogenic according to our data. Variant chr20-6097571-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 224173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-6097571-C-A is described in Lovd as [Pathogenic]. Variant chr20-6097571-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FERMT1	NM_017671.5 link	c.910G>T	p.Glu304*	stop_gained	7/15	ENST00000217289.9	NP_060141.3	Q9BQL6-1Q54A15Q49AC8
FERMT1	XM_024451935.2 link	c.910G>T	p.Glu304*	stop_gained	7/15		XP_024307703.1
FERMT1	XM_047440259.1 link	c.910G>T	p.Glu304*	stop_gained	7/15		XP_047296215.1
FERMT1	XM_047440260.1 link	c.625G>T	p.Glu209*	stop_gained	6/14		XP_047296216.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FERMT1	ENST00000217289.9 link	c.910G>T	p.Glu304*	stop_gained	7/15	1	NM_017671.5	ENSP00000217289.4		Q9BQL6-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000637

AC:

AN:

251350

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135842

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000123

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000133

AC:

194

AN:

1461830

Hom.:

Cov.:

AF XY:

0.000113

AC XY:

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

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:

0.000166

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000944

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000118

Hom.:

Bravo

AF:

0.0000453

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Kindler syndrome

Pathogenic:1Other:1

not provided, no classification provided	literature only	GeneReviews	-	Common pathogenic variant -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 24, 2017	The FERMT1 c.910G>T (p.Glu304Ter) variant is a stop-gained variant reported in a total of ten individuals with Kindler syndrome, including five homozygotes and five compound heterozygotes (Lanschuetzer et al. 2003; Lai-Cheong et al. 2008; Has et al. 2009; Techanukul et al. 2011; Youssefian et al. 2015). The variant was absent from a total of 200 control chromosomes but is reported at a frequency of 0.00012 in the European (non-Finnish) population of the Exome Aggregation Consortium. Has et al. (2009) showed that expression of kindlin-1, the protein produced by FERMT1, was absent in primary keratinocytes from a individual homozygous for the p.Glu304Ter variant as well as a individual compound heterozygous for p.Glu304Ter and a second stop-gained variant. Based on the potential impact of stop-gained variants and the evidence from the literature, the p.Glu304Ter variant is classified as pathogenic for Kindler syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

FERMT1-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 01, 2024

The FERMT1 c.910G>T variant is predicted to result in premature protein termination (p.Glu304*). This variant has been reported in the homozygous or compound heterozygous state in individuals affected with Kindler syndrome (see for example, Lanschuetzer et al. 2003. PubMed ID: 14507403; Has et al. 2009. PubMed ID: 19762715; Lai-Cheong et al. 2009. PubMed ID: 19762710; Heinemann et al. 2011. PubMed ID: 21309038). This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in FERMT1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 15, 2024

This sequence change creates a premature translational stop signal (p.Glu304*) in the FERMT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FERMT1 are known to be pathogenic (PMID: 14962093, 21936020). This variant is present in population databases (rs146180696, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with clinical features of Kindler syndrome (PMID: 14507403). ClinVar contains an entry for this variant (Variation ID: 224173). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.63

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.94

FATHMM_MKL

Uncertain

0.95

Vest4

0.78

GERP RS

5.6

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

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