20-6075104-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_017671.5(FERMT1):c.*2069T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.28 in 146,794 control chromosomes in the GnomAD database, including 6,112 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.28 (6108 hom., cov: 27)
  • Exomes 𝑓: 0.20 (4 hom.)
• Consequence: FERMT1 NM_017671.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.92

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 20-6075104-A-G is Benign according to our data. Variant chr20-6075104-A-G is described in ClinVar as [Benign]. Clinvar id is 339174.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.55 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FERMT1	NM_017671.5	c.*2069T>C		3_prime_UTR_variant	15/15	ENST00000217289.9
FERMT1	XM_024451935.2	c.*2069T>C		3_prime_UTR_variant	15/15
FERMT1	XM_047440259.1	c.*2069T>C		3_prime_UTR_variant	15/15
FERMT1	XM_047440260.1	c.*2069T>C		3_prime_UTR_variant	14/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FERMT1	ENST00000217289.9	c.*2069T>C		3_prime_UTR_variant	15/15	1	NM_017671.5	P1
FERMT1	ENST00000478194.1	n.3063T>C		non_coding_transcript_exon_variant	7/7	1

Frequencies

GnomAD3 genomes AF: 0.280 AC: 41035 AN: 146544 Hom.: 6091 Cov.: 27

Gnomad AFR AF: 0.317

Gnomad AMI AF: 0.213

Gnomad AMR AF: 0.362

Gnomad ASJ AF: 0.222

Gnomad EAS AF: 0.567

Gnomad SAS AF: 0.335

Gnomad FIN AF: 0.156

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.236

Gnomad OTH AF: 0.297

GnomAD4 exome AF: 0.201 AC: 27 AN: 134 Hom.: 4 Cov.: 0 AF XY: 0.176 AC XY: 13 AN XY: 74

Gnomad4 EAS exome AF: 0.201

GnomAD4 genome AF: 0.280 AC: 41098 AN: 146660 Hom.: 6108 Cov.: 27 AF XY: 0.282 AC XY: 20028 AN XY: 70994

Gnomad4 AFR AF: 0.318

Gnomad4 AMR AF: 0.362

Gnomad4 ASJ AF: 0.222

Gnomad4 EAS AF: 0.568

Gnomad4 SAS AF: 0.334

Gnomad4 FIN AF: 0.156

Gnomad4 NFE AF: 0.236

Gnomad4 OTH AF: 0.304

Alfa AF: 0.246 Hom.: 3503

Bravo AF: 0.295

Asia WGS AF: 0.450 AC: 1564 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Kindler syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	0.14
Dann	Benign	0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1059396; hg19: chr20-6055751;