20-6075045-G-GT

Variant names:

• chr20-6075045-G-GT
• rs139990090
• ENST00000478194.1:n.3121dupA

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_017671.5(FERMT1):​c.*2127dupA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 133,236 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0013 (4 hom., cov: 31)
  • Exomes 𝑓: 0.0079 (0 hom.)
• Consequence: FERMT1 NM_017671.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.90
• Publications: 1 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: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00134 (178/133110) while in subpopulation EAS AF = 0.00771 (36/4668). AF 95% confidence interval is 0.00573. There are 4 homozygotes in GnomAd4. There are 93 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FERMT1	NM_017671.5	c.*2127dupA		3_prime_UTR_variant	Exon 15 of 15	ENST00000217289.9	NP_060141.3
FERMT1	XM_024451935.2	c.*2127dupA		3_prime_UTR_variant	Exon 15 of 15		XP_024307703.1
FERMT1	XM_047440259.1	c.*2127dupA		3_prime_UTR_variant	Exon 15 of 15		XP_047296215.1
FERMT1	XM_047440260.1	c.*2127dupA		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.3121dupA		non_coding_transcript_exon_variant	Exon 7 of 7	1
FERMT1	ENST00000217289.9	c.*2127dupA		3_prime_UTR_variant	Exon 15 of 15	1	NM_017671.5	ENSP00000217289.4

Frequencies

GnomAD3 genomes AF: 0.00134 AC: 178 AN: 133072 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.000696

Gnomad AMI AF: 0.00694

Gnomad AMR AF: 0.00199

Gnomad ASJ AF: 0.000917

Gnomad EAS AF: 0.00790

Gnomad SAS AF: 0.00192

Gnomad FIN AF: 0.000551

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00107

Gnomad OTH AF: 0.00162

GnomAD4 exome AF: 0.00794 AC: 1 AN: 126 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 68

⚠️ 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: 0.00794 AC: 1 AN: 126

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: 0.00134 AC: 178 AN: 133110 Hom.: 4 Cov.: 31 AF XY: 0.00145 AC XY: 93 AN XY: 64272

African (AFR) AF: 0.000694 AC: 25 AN: 36018

American (AMR) AF: 0.00199 AC: 26 AN: 13046

Ashkenazi Jewish (ASJ) AF: 0.000917 AC: 3 AN: 3272

East Asian (EAS) AF: 0.00771 AC: 36 AN: 4668

South Asian (SAS) AF: 0.00192 AC: 8 AN: 4162

European-Finnish (FIN) AF: 0.000551 AC: 4 AN: 7260

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 270

European-Non Finnish (NFE) AF: 0.00107 AC: 66 AN: 61692

Other (OTH) AF: 0.00215 AC: 4 AN: 1858

Alfa AF: 0.000491 Hom.: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Kindler syndrome Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.9
Mutation Taster		=100/0	polymorphism

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: rs139990090; hg19: chr20-6055692;