rs2232073

chr20-6085084-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_017671.5(FERMT1):c.1575A>G(p.Lys525=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.385 in 1,611,858 control chromosomes in the GnomAD database, including 123,102 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (13259 hom., cov: 32)
  • Exomes 𝑓: 0.38 (109843 hom.)
• Consequence: FERMT1 NM_017671.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.13

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 20-6085084-T-C is Benign according to our data. Variant chr20-6085084-T-C is described in ClinVar as [Benign]. Clinvar id is 260866.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-6085084-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.13 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.621 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FERMT1	NM_017671.5	c.1575A>G	p.Lys525=	synonymous_variant	12/15	ENST00000217289.9
FERMT1	XM_024451935.2	c.1575A>G	p.Lys525=	synonymous_variant	12/15
FERMT1	XM_047440259.1	c.1575A>G	p.Lys525=	synonymous_variant	12/15
FERMT1	XM_047440260.1	c.1290A>G	p.Lys430=	synonymous_variant	11/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FERMT1	ENST00000217289.9	c.1575A>G	p.Lys525=	synonymous_variant	12/15	1	NM_017671.5	P1
FERMT1	ENST00000478194.1	n.535A>G		non_coding_transcript_exon_variant	4/7	1
FERMT1	ENST00000536936.1	c.*1077A>G		3_prime_UTR_variant, NMD_transcript_variant	11/14	1
FERMT1	ENST00000699095.1	c.1575A>G	p.Lys525=	synonymous_variant	11/14			P1

Frequencies

GnomAD3 genomes AF: 0.412 AC: 62447 AN: 151568 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

GnomAD3 exomes AF: 0.404 AC: 101621 AN: 251396 Hom.: 21746 AF XY: 0.395 AC XY: 53602 AN XY: 135862

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 SAS exome AF: 0.328

Gnomad FIN exome AF: 0.273

Gnomad NFE exome AF: 0.370

Gnomad OTH exome AF: 0.393

GnomAD4 exome AF: 0.383 AC: 558652 AN: 1460172 Hom.: 109843 Cov.: 36 AF XY: 0.381 AC XY: 276750 AN XY: 726506

Gnomad4 AFR exome AF: 0.458

Gnomad4 AMR exome AF: 0.502

Gnomad4 ASJ exome AF: 0.424

Gnomad4 EAS exome AF: 0.648

Gnomad4 SAS exome AF: 0.328

Gnomad4 FIN exome AF: 0.276

Gnomad4 NFE exome AF: 0.373

Gnomad4 OTH exome AF: 0.402

GnomAD4 genome AF: 0.412 AC: 62506 AN: 151686 Hom.: 13259 Cov.: 32 AF XY: 0.410 AC XY: 30396 AN XY: 74110

Gnomad4 AFR AF: 0.458

Gnomad4 AMR AF: 0.483

Gnomad4 ASJ AF: 0.420

Gnomad4 EAS AF: 0.639

Gnomad4 SAS AF: 0.334

Gnomad4 FIN AF: 0.273

Gnomad4 NFE AF: 0.377

Gnomad4 OTH AF: 0.442

Alfa AF: 0.392 Hom.: 7701

Bravo AF: 0.434

Asia WGS AF: 0.488 AC: 1695 AN: 3478

EpiCase AF: 0.389

EpiControl AF: 0.382

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Kindler syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
Cadd	Benign	4.3
Dann	Benign	0.54

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: rs2232073; hg19: chr20-6065731; COSMIC: COSV54093616;