rs2232074

Variant names:

• chr20-6085082-C-T
• rs2232074
• NM_017671.5:c.1577G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_017671.5(FERMT1):​c.1577G>A​(p.Arg526Lys) variant causes a missense change. The variant allele was found at a frequency of 0.385 in 1,611,632 control chromosomes in the GnomAD database, including 123,094 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.41 (13259 hom., cov: 32)
  • Exomes 𝑓: 0.38 (109835 hom.)
• Consequence: FERMT1 NM_017671.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 6.21
• Publications: 33 publications found

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 Gene-Disease associations (from GenCC):

• Kindler syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.15422E-5).
• BP6: Variant 20-6085082-C-T is Benign according to our data. Variant chr20-6085082-C-T is described in ClinVar as Benign. ClinVar VariationId is 260867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.62 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FERMT1	NM_017671.5	c.1577G>A	p.Arg526Lys	missense_variant	Exon 12 of 15	ENST00000217289.9	NP_060141.3
FERMT1	XM_024451935.2	c.1577G>A	p.Arg526Lys	missense_variant	Exon 12 of 15		XP_024307703.1
FERMT1	XM_047440259.1	c.1577G>A	p.Arg526Lys	missense_variant	Exon 12 of 15		XP_047296215.1
FERMT1	XM_047440260.1	c.1292G>A	p.Arg431Lys	missense_variant	Exon 11 of 14		XP_047296216.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FERMT1	ENST00000217289.9	c.1577G>A	p.Arg526Lys	missense_variant	Exon 12 of 15	1	NM_017671.5	ENSP00000217289.4

Frequencies

GnomAD3 genomes AF: 0.412 AC: 62446 AN: 151540 Hom.: 13241 Cov.: 32

Gnomad AFR AF: 0.458

Gnomad AMI AF: 0.404

Gnomad AMR AF: 0.483

Gnomad ASJ AF: 0.420

Gnomad EAS AF: 0.638

Gnomad SAS AF: 0.336

Gnomad FIN AF: 0.273

Gnomad MID AF: 0.433

Gnomad NFE AF: 0.377

Gnomad OTH AF: 0.437

GnomAD2 exomes AF: 0.404 AC: 101608 AN: 251378 AF XY: 0.395

Gnomad AFR exome AF: 0.456

Gnomad AMR exome AF: 0.506

Gnomad ASJ exome AF: 0.431

Gnomad EAS exome AF: 0.651

Gnomad FIN exome AF: 0.273

Gnomad NFE exome AF: 0.370

Gnomad OTH exome AF: 0.393

GnomAD4 exome AF: 0.383 AC: 558558 AN: 1459974 Hom.: 109835 Cov.: 36 AF XY: 0.381 AC XY: 276713 AN XY: 726422

African (AFR) AF: 0.458 AC: 15298 AN: 33438

American (AMR) AF: 0.501 AC: 22427 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.424 AC: 11083 AN: 26130

East Asian (EAS) AF: 0.648 AC: 25699 AN: 39688

South Asian (SAS) AF: 0.328 AC: 28236 AN: 86214

European-Finnish (FIN) AF: 0.276 AC: 14721 AN: 53414

Middle Eastern (MID) AF: 0.417 AC: 2404 AN: 5768

European-Non Finnish (NFE) AF: 0.373 AC: 414425 AN: 1110286

Other (OTH) AF: 0.402 AC: 24265 AN: 60312

GnomAD4 genome AF: 0.412 AC: 62505 AN: 151658 Hom.: 13259 Cov.: 32 AF XY: 0.410 AC XY: 30397 AN XY: 74100

African (AFR) AF: 0.458 AC: 18898 AN: 41280

American (AMR) AF: 0.483 AC: 7370 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.420 AC: 1456 AN: 3466

East Asian (EAS) AF: 0.639 AC: 3274 AN: 5126

South Asian (SAS) AF: 0.334 AC: 1610 AN: 4822

European-Finnish (FIN) AF: 0.273 AC: 2877 AN: 10534

Middle Eastern (MID) AF: 0.445 AC: 130 AN: 292

European-Non Finnish (NFE) AF: 0.377 AC: 25592 AN: 67866

Other (OTH) AF: 0.441 AC: 930 AN: 2108

Alfa AF: 0.397 Hom.: 23436

Bravo AF: 0.434

TwinsUK AF: 0.363 AC: 1345

ALSPAC AF: 0.372 AC: 1434

ESP6500AA AF: 0.0842 AC: 371

ESP6500EA AF: 0.0516 AC: 444

ExAC AF: 0.398 AC: 48296

Asia WGS AF: 0.488 AC: 1695 AN: 3478

EpiCase AF: 0.389

EpiControl AF: 0.382

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 74% of patients studied by a panel of primary immunodeficiencies. Number of patients: 65. Only high quality variants are reported. -

Kindler syndrome Benign:2

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	17
DANN	Benign	0.63
DEOGEN2	Benign	0.15	T;.
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.51	T;T
MetaRNN	Benign	0.000022	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-2.4	N;.
PhyloP100		6.2
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	2.4	N;N
REVEL	Benign	0.19
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;.
Vest4		0.089
MPC		0.26
ClinPred		0.017	T
GERP RS		5.2
Varity_R		0.076
gMVP		0.26
Mutation Taster		=95/5	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2232074; hg19: chr20-6065729; COSMIC: COSV54093600;