20-6084063-A-G

Variant names:

• chr20-6084063-A-G
• rs753927
• NM_017671.5:c.1695T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000217289.9(FERMT1):​c.1695T>C​(p.Phe565Phe) 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 ENST00000217289.9 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.118
• Publications: 23 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 -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 VariationId is 260868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000217289.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FERMT1	NM_017671.5	MANE Select	c.1695T>C	p.Phe565Phe	synonymous	Exon 13 of 15	NP_060141.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FERMT1	ENST00000217289.9	TSL:1 MANE Select	c.1695T>C	p.Phe565Phe	synonymous	Exon 13 of 15	ENSP00000217289.4
	FERMT1	ENST00000478194.1	TSL:1	n.655T>C		non_coding_transcript_exon	Exon 5 of 7
	FERMT1	ENST00000536936.1	TSL:1	n.*1197T>C		non_coding_transcript_exon	Exon 12 of 14	ENSP00000441063.2

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

GnomAD2 exomes AF: 0.376 AC: 94290 AN: 250470 AF XY: 0.367

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 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

African (AFR) AF: 0.344 AC: 11518 AN: 33446

American (AMR) AF: 0.482 AC: 21516 AN: 44620

Ashkenazi Jewish (ASJ) AF: 0.373 AC: 9746 AN: 26128

East Asian (EAS) AF: 0.636 AC: 25219 AN: 39662

South Asian (SAS) AF: 0.275 AC: 23667 AN: 86180

European-Finnish (FIN) AF: 0.274 AC: 14591 AN: 53344

Middle Eastern (MID) AF: 0.372 AC: 2146 AN: 5764

European-Non Finnish (NFE) AF: 0.360 AC: 399804 AN: 1110418

Other (OTH) AF: 0.372 AC: 22418 AN: 60324

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

African (AFR) AF: 0.350 AC: 14550 AN: 41516

American (AMR) AF: 0.456 AC: 6969 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.371 AC: 1285 AN: 3468

East Asian (EAS) AF: 0.619 AC: 3195 AN: 5164

South Asian (SAS) AF: 0.281 AC: 1357 AN: 4830

European-Finnish (FIN) AF: 0.273 AC: 2887 AN: 10578

Middle Eastern (MID) AF: 0.388 AC: 114 AN: 294

European-Non Finnish (NFE) AF: 0.365 AC: 24790 AN: 67998

Other (OTH) AF: 0.393 AC: 827 AN: 2106

Alfa AF: 0.371 Hom.: 43373

Bravo AF: 0.387

Asia WGS AF: 0.445 AC: 1548 AN: 3478

EpiCase AF: 0.372

EpiControl AF: 0.363

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Kindler syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	1.2
DANN	Benign	0.65
PhyloP100		0.12
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=94/6	polymorphism (auto)

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

Other links and lift over

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