chr20-6075115-G-A

Variant names:

• chr20-6075115-G-A
• rs12945
• ENST00000478194.1:n.3052C>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.*2058C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.229 in 148,910 control chromosomes in the GnomAD database, including 4,312 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4308 hom., cov: 28)
  • Exomes 𝑓: 0.18 (4 hom.)
• Consequence: FERMT1 NM_017671.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.272
• Publications: 7 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=-0.82).
• BP6: Variant 20-6075115-G-A is Benign according to our data. Variant chr20-6075115-G-A is described in ClinVar as [Benign]. Clinvar id is 339176.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.539 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FERMT1	NM_017671.5	c.*2058C>T		3_prime_UTR_variant	Exon 15 of 15	ENST00000217289.9	NP_060141.3
FERMT1	XM_024451935.2	c.*2058C>T		3_prime_UTR_variant	Exon 15 of 15		XP_024307703.1
FERMT1	XM_047440259.1	c.*2058C>T		3_prime_UTR_variant	Exon 15 of 15		XP_047296215.1
FERMT1	XM_047440260.1	c.*2058C>T		3_prime_UTR_variant	Exon 14 of 14		XP_047296216.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FERMT1	ENST00000478194.1	n.3052C>T		non_coding_transcript_exon_variant	Exon 7 of 7	1
FERMT1	ENST00000217289.9	c.*2058C>T		3_prime_UTR_variant	Exon 15 of 15	1	NM_017671.5	ENSP00000217289.4

Frequencies

GnomAD3 genomes AF: 0.229 AC: 34081 AN: 148662 Hom.: 4302 Cov.: 28

Gnomad AFR AF: 0.194

Gnomad AMI AF: 0.210

Gnomad AMR AF: 0.325

Gnomad ASJ AF: 0.186

Gnomad EAS AF: 0.555

Gnomad SAS AF: 0.233

Gnomad FIN AF: 0.148

Gnomad MID AF: 0.205

Gnomad NFE AF: 0.219

Gnomad OTH AF: 0.241

GnomAD4 exome AF: 0.184 AC: 25 AN: 136 Hom.: 4 Cov.: 0 AF XY: 0.171 AC XY: 13 AN XY: 76

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.184 AC: 25 AN: 136

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.229 AC: 34115 AN: 148774 Hom.: 4308 Cov.: 28 AF XY: 0.230 AC XY: 16607 AN XY: 72332

African (AFR) AF: 0.194 AC: 7796 AN: 40282

American (AMR) AF: 0.325 AC: 4826 AN: 14866

Ashkenazi Jewish (ASJ) AF: 0.186 AC: 641 AN: 3440

East Asian (EAS) AF: 0.556 AC: 2779 AN: 5000

South Asian (SAS) AF: 0.232 AC: 1094 AN: 4708

European-Finnish (FIN) AF: 0.148 AC: 1450 AN: 9790

Middle Eastern (MID) AF: 0.214 AC: 62 AN: 290

European-Non Finnish (NFE) AF: 0.219 AC: 14771 AN: 67448

Other (OTH) AF: 0.247 AC: 508 AN: 2054

Alfa AF: 0.226 Hom.: 4026

Bravo AF: 0.242

Asia WGS AF: 0.397 AC: 1379 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Kindler syndrome Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.1
DANN	Benign	0.26
PhyloP100		0.27
Mutation Taster		=100/0	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: rs12945; hg19: chr20-6055762;