chr20-6119583-A-C

Position:

• chr20-6119583-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_017671.5(FERMT1):​c.-18-11T>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.597 in 1,604,058 control chromosomes in the GnomAD database, including 290,809 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.61 (29014 hom., cov: 32)
  • Exomes 𝑓: 0.60 (261795 hom.)
• Consequence: FERMT1 NM_017671.5 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.05339
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0650

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 20-6119583-A-C is Benign according to our data. Variant chr20-6119583-A-C is described in ClinVar as [Benign]. Clinvar id is 260863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.823 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FERMT1	NM_017671.5	c.-18-11T>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000217289.9
FERMT1	XM_047440259.1	c.-29T>G		5_prime_UTR_variant	2/15
FERMT1	XM_024451935.2	c.-21-8T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FERMT1	ENST00000217289.9	c.-18-11T>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_017671.5	P1

Frequencies

GnomAD3 genomes AF: 0.613 AC: 93163 AN: 151878 Hom.: 28977 Cov.: 32

Gnomad AFR AF: 0.642

Gnomad AMI AF: 0.612

Gnomad AMR AF: 0.662

Gnomad ASJ AF: 0.676

Gnomad EAS AF: 0.844

Gnomad SAS AF: 0.764

Gnomad FIN AF: 0.442

Gnomad MID AF: 0.728

Gnomad NFE AF: 0.578

Gnomad OTH AF: 0.657

GnomAD3 exomes AF: 0.628 AC: 151368 AN: 240944 Hom.: 48563 AF XY: 0.634 AC XY: 82652 AN XY: 130322

Gnomad AFR exome AF: 0.635

Gnomad AMR exome AF: 0.638

Gnomad ASJ exome AF: 0.680

Gnomad EAS exome AF: 0.847

Gnomad SAS exome AF: 0.762

Gnomad FIN exome AF: 0.447

Gnomad NFE exome AF: 0.580

Gnomad OTH exome AF: 0.642

GnomAD4 exome AF: 0.595 AC: 864530 AN: 1452062 Hom.: 261795 Cov.: 33 AF XY: 0.601 AC XY: 433829 AN XY: 722222

Gnomad4 AFR exome AF: 0.648

Gnomad4 AMR exome AF: 0.640

Gnomad4 ASJ exome AF: 0.677

Gnomad4 EAS exome AF: 0.857

Gnomad4 SAS exome AF: 0.753

Gnomad4 FIN exome AF: 0.453

Gnomad4 NFE exome AF: 0.574

Gnomad4 OTH exome AF: 0.616

GnomAD4 genome AF: 0.614 AC: 93250 AN: 151996 Hom.: 29014 Cov.: 32 AF XY: 0.614 AC XY: 45634 AN XY: 74316

Gnomad4 AFR AF: 0.643

Gnomad4 AMR AF: 0.661

Gnomad4 ASJ AF: 0.676

Gnomad4 EAS AF: 0.844

Gnomad4 SAS AF: 0.763

Gnomad4 FIN AF: 0.442

Gnomad4 NFE AF: 0.578

Gnomad4 OTH AF: 0.660

Alfa AF: 0.607 Hom.: 6485

Bravo AF: 0.627

Asia WGS AF: 0.776 AC: 2699 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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 90% of patients studied by a panel of primary immunodeficiencies. Number of patients: 79. Only high quality variants are reported. -

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:1

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	-0.79
CADD	Benign	1.8
DANN	Benign	0.76
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.053
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: rs2273423; hg19: chr20-6100230; COSMIC: COSV104372289;