rs121918294

Positions:

• chr20-6097619-G-A
• chr20-6097619-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_017671.5(FERMT1):​c.862C>T​(p.Arg288Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,612,098 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 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: FERMT1 NM_017671.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 1.30

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]

ACMG classification

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 20-6097619-G-A is Pathogenic according to our data. Variant chr20-6097619-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2718.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-6097619-G-A is described in Lovd as [Pathogenic]. Variant chr20-6097619-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FERMT1	NM_017671.5	c.862C>T	p.Arg288Ter	stop_gained	7/15	ENST00000217289.9	NP_060141.3
FERMT1	XM_024451935.2	c.862C>T	p.Arg288Ter	stop_gained	7/15		XP_024307703.1
FERMT1	XM_047440259.1	c.862C>T	p.Arg288Ter	stop_gained	7/15		XP_047296215.1
FERMT1	XM_047440260.1	c.577C>T	p.Arg193Ter	stop_gained	6/14		XP_047296216.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FERMT1	ENST00000217289.9	c.862C>T	p.Arg288Ter	stop_gained	7/15	1	NM_017671.5	ENSP00000217289	P1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151882 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1460216 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726566

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151882 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74170

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Kindler syndrome Pathogenic:2 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2003	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Mar 03, 2022	This sequence change in FERMT1 is a nonsense variant predicted to cause a premature stop codon, p.(Arg288*), in biologically-relevant-exon 7/15 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PMID: 26937547). The highest population minor allele frequency in gnomAD v3.1 is 0.002% (1/41,324 alleles) in the African/African American population, which is consistent with recessive disease. This variant has been detected homozygous in at least three individuals with Kindler syndrome from unrelated consanguineous families (PMID: 12789646, 24635075). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PM2_Supporting, PM3_Supporting. -
not provided, no classification provided	literature only	GeneReviews	-	Common pathogenic variant -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 03, 2022

This sequence change creates a premature translational stop signal (p.Arg288*) 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 not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 2718). This premature translational stop signal has been observed in individual(s) with Kindler syndrome (PMID: 12789646). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.82	D
MutationTaster	Benign	1.0	A;A
Vest4		0.93
GERP RS		2.2

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

LitVar

Other links and lift over

dbSNP: rs121918294; hg19: chr20-6078266; COSMIC: COSV105094617; COSMIC: COSV105094617;