rs2273423

Variant names:

• chr20-6119583-A-C
• rs2273423
• NM_017671.5:c.-18-11T>G

Your query was ambiguous. Multiple possible variants found:

• chr20-6119583-A-C
• chr20-6119583-A-T

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.-18-11T>G variant causes a 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 intron
• Scores: Splicing: ADA: 0.05339
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0650
• Publications: 14 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 (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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017671.5. 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.-18-11T>G		intron	N/A	NP_060141.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FERMT1	ENST00000217289.9	TSL:1 MANE Select	c.-18-11T>G		intron	N/A	ENSP00000217289.4
	FERMT1	ENST00000536936.1	TSL:1	n.-18-11T>G		intron	N/A	ENSP00000441063.2
	FERMT1	ENST00000699095.1		c.-29T>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 14	ENSP00000514127.1

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

GnomAD2 exomes AF: 0.628 AC: 151368 AN: 240944 AF XY: 0.634

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 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

African (AFR) AF: 0.648 AC: 21551 AN: 33238

American (AMR) AF: 0.640 AC: 27969 AN: 43704

Ashkenazi Jewish (ASJ) AF: 0.677 AC: 17616 AN: 26038

East Asian (EAS) AF: 0.857 AC: 33886 AN: 39542

South Asian (SAS) AF: 0.753 AC: 64498 AN: 85666

European-Finnish (FIN) AF: 0.453 AC: 24003 AN: 53018

Middle Eastern (MID) AF: 0.718 AC: 4124 AN: 5744

European-Non Finnish (NFE) AF: 0.574 AC: 633904 AN: 1105034

Other (OTH) AF: 0.616 AC: 36979 AN: 60078

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

African (AFR) AF: 0.643 AC: 26628 AN: 41440

American (AMR) AF: 0.661 AC: 10100 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.676 AC: 2345 AN: 3470

East Asian (EAS) AF: 0.844 AC: 4365 AN: 5170

South Asian (SAS) AF: 0.763 AC: 3678 AN: 4818

European-Finnish (FIN) AF: 0.442 AC: 4661 AN: 10554

Middle Eastern (MID) AF: 0.735 AC: 216 AN: 294

European-Non Finnish (NFE) AF: 0.578 AC: 39305 AN: 67950

Other (OTH) AF: 0.660 AC: 1394 AN: 2112

Alfa AF: 0.607 Hom.: 6485

Bravo AF: 0.627

Asia WGS AF: 0.776 AC: 2699 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.8
DANN	Benign	0.76
PhyloP100		0.065
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2273423; hg19: chr20-6100230; COSMIC: COSV104372289;