rs753927

chr20-6084063-A-Gchr20-6084063-A-T

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.1695T>C(p.Phe565=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.364 in 1,612,042 control chromosomes in the GnomAD database, including 110,378 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (10836 hom., cov: 33)
  • Exomes 𝑓: 0.36 (99542 hom.)
• Consequence: FERMT1 NM_017671.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.118

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=-0.47).
• BP6: Variant 20-6084063-A-G is Benign according to our data. Variant chr20-6084063-A-G is described in ClinVar as [Benign]. Clinvar id is 260868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-6084063-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.118 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.601 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FERMT1	NM_017671.5	c.1695T>C	p.Phe565=	synonymous_variant	13/15	ENST00000217289.9
FERMT1	XM_024451935.2	c.1695T>C	p.Phe565=	synonymous_variant	13/15
FERMT1	XM_047440259.1	c.1695T>C	p.Phe565=	synonymous_variant	13/15
FERMT1	XM_047440260.1	c.1410T>C	p.Phe470=	synonymous_variant	12/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FERMT1	ENST00000217289.9	c.1695T>C	p.Phe565=	synonymous_variant	13/15	1	NM_017671.5	P1
FERMT1	ENST00000478194.1	n.655T>C		non_coding_transcript_exon_variant	5/7	1
FERMT1	ENST00000536936.1	c.*1197T>C		3_prime_UTR_variant, NMD_transcript_variant	12/14	1
FERMT1	ENST00000699095.1	c.1695T>C	p.Phe565=	synonymous_variant	12/14			P1

Frequencies

GnomAD3 genomes AF: 0.370 AC: 56313 AN: 152038 Hom.: 10824 Cov.: 33

Gnomad AFR AF: 0.351

Gnomad AMI AF: 0.416

Gnomad AMR AF: 0.456

Gnomad ASJ AF: 0.371

Gnomad EAS AF: 0.617

Gnomad SAS AF: 0.283

Gnomad FIN AF: 0.273

Gnomad MID AF: 0.386

Gnomad NFE AF: 0.365

Gnomad OTH AF: 0.387

GnomAD3 exomes AF: 0.376 AC: 94290 AN: 250470 Hom.: 18941 AF XY: 0.367 AC XY: 49616 AN XY: 135348

Gnomad AFR exome AF: 0.342

Gnomad AMR exome AF: 0.488

Gnomad ASJ exome AF: 0.380

Gnomad EAS exome AF: 0.630

Gnomad SAS exome AF: 0.274

Gnomad FIN exome AF: 0.271

Gnomad NFE exome AF: 0.355

Gnomad OTH exome AF: 0.366

GnomAD4 exome AF: 0.363 AC: 530625 AN: 1459886 Hom.: 99542 Cov.: 41 AF XY: 0.361 AC XY: 262202 AN XY: 726364

Gnomad4 AFR exome AF: 0.344

Gnomad4 AMR exome AF: 0.482

Gnomad4 ASJ exome AF: 0.373

Gnomad4 EAS exome AF: 0.636

Gnomad4 SAS exome AF: 0.275

Gnomad4 FIN exome AF: 0.274

Gnomad4 NFE exome AF: 0.360

Gnomad4 OTH exome AF: 0.372

GnomAD4 genome AF: 0.370 AC: 56353 AN: 152156 Hom.: 10836 Cov.: 33 AF XY: 0.370 AC XY: 27486 AN XY: 74380

Gnomad4 AFR AF: 0.350

Gnomad4 AMR AF: 0.456

Gnomad4 ASJ AF: 0.371

Gnomad4 EAS AF: 0.619

Gnomad4 SAS AF: 0.281

Gnomad4 FIN AF: 0.273

Gnomad4 NFE AF: 0.365

Gnomad4 OTH AF: 0.393

Alfa AF: 0.373 Hom.: 20281

Bravo AF: 0.387

Asia WGS AF: 0.445 AC: 1548 AN: 3478

EpiCase AF: 0.372

EpiControl AF: 0.363

ClinVar

Significance: Benign

Submissions summary: Benign:4

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 72% of patients studied by a panel of primary immunodeficiencies. Number of patients: 63. Only high quality variants are reported. -

Kindler syndrome Benign:1

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
Cadd	Benign	1.2
Dann	Benign	0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs753927; hg19: chr20-6064710; COSMIC: COSV54098214;