rs869312727

Variant names:

• chr20-6094937-A-G
• rs869312727
• NM_017671.5:c.1139+2T>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_017671.5(FERMT1):​c.1139+2T>C variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FERMT1 NM_017671.5 splice_donor, intron
• Scores: Splicing: ADA: 0.9921
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 8.06
• Publications: 2 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FERMT1	NM_017671.5	c.1139+2T>C		splice_donor_variant, intron_variant	Intron 9 of 14	ENST00000217289.9	NP_060141.3
FERMT1	XM_024451935.2	c.1139+2T>C		splice_donor_variant, intron_variant	Intron 9 of 14		XP_024307703.1
FERMT1	XM_047440259.1	c.1139+2T>C		splice_donor_variant, intron_variant	Intron 9 of 14		XP_047296215.1
FERMT1	XM_047440260.1	c.854+2T>C		splice_donor_variant, intron_variant	Intron 8 of 13		XP_047296216.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FERMT1	ENST00000217289.9	c.1139+2T>C		splice_donor_variant, intron_variant	Intron 9 of 14	1	NM_017671.5	ENSP00000217289.4
FERMT1	ENST00000536936.1	n.*641+2T>C		splice_donor_variant, intron_variant	Intron 8 of 13	1		ENSP00000441063.2
FERMT1	ENST00000699095.1	c.1139+2T>C		splice_donor_variant, intron_variant	Intron 8 of 13			ENSP00000514127.1
FERMT1	ENST00000699096.1	n.1601+2T>C		splice_donor_variant, intron_variant	Intron 9 of 10

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1311082 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 660700

African (AFR) AF: 0.00 AC: 0 AN: 30650

American (AMR) AF: 0.00 AC: 0 AN: 44496

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25150

East Asian (EAS) AF: 0.00 AC: 0 AN: 38966

South Asian (SAS) AF: 0.00 AC: 0 AN: 83014

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53356

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5510

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 974742

Other (OTH) AF: 0.00 AC: 0 AN: 55198

GnomAD4 genome Cov.: 33

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Kindler syndrome Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	27
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		8.1
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Benign	0.66
SpliceAI score (max)		0.75		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.75		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs869312727; hg19: chr20-6075584;