Genetic Variant NM_017671.5:c.*2124delC (chr20-6075048-TG-T) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_SupportingBS2

The NM_017671.5(FERMT1):c.*2124delC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0123 in 137,926 control chromosomes in the GnomAD database, including 43 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.012 ( 43 hom., cov: 23)

Exomes 𝑓: 0.0082 ( 0 hom. )

Consequence

FERMT1
NM_017671.5 3_prime_UTR

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.13

Publications

0 publications found

Variant links:

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: G2P, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics

FERMT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0123 (1701/137804) while in subpopulation AFR AF = 0.0426 (1478/34660). AF 95% confidence interval is 0.0408. There are 43 homozygotes in GnomAd4. There are 756 alleles in the male GnomAd4 subpopulation. Median coverage is 23. 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 43 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FERMT1	NM_017671.5	MANE Select	c.*2124delC		3_prime_UTR	Exon 15 of 15	NP_060141.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
FERMT1	ENST00000217289.9	TSL:1 MANE Select	c.*2124delC	3_prime_UTR	Exon 15 of 15	ENSP00000217289.4	Q9BQL6-1
FERMT1	ENST00000478194.1	TSL:1	n.3118delC	non_coding_transcript_exon	Exon 7 of 7
FERMT1	ENST00000855451.1		c.*2124delC	3_prime_UTR	Exon 15 of 15	ENSP00000525510.1

Frequencies

GnomAD3 genomes

AF:

0.0124

AC:

1702

AN:

137726

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0428

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00509

Gnomad ASJ

AF:

0.000607

Gnomad EAS

AF:

0.00554

Gnomad SAS

AF:

0.00179

Gnomad FIN

AF:

0.000776

Gnomad MID

AF:

0.00962

Gnomad NFE

AF:

0.00138

Gnomad OTH

AF:

0.00846

GnomAD4 exome

AF:

0.00820

AC:

AN:

122

Hom.:

Cov.:

AF XY:

0.0139

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

0.00820

AC:

AN:

122

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AC:

AN:

Other (OTH)

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.775

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0123

AC:

1701

AN:

137804

Hom.:

Cov.:

AF XY:

0.0113

AC XY:

756

AN XY:

67060

show subpopulations

African (AFR)

AF:

0.0426

AC:

1478

AN:

34660

American (AMR)

AF:

0.00508

AC:

AN:

13776

Ashkenazi Jewish (ASJ)

AF:

0.000607

AC:

AN:

3296

East Asian (EAS)

AF:

0.00555

AC:

AN:

5046

South Asian (SAS)

AF:

0.00179

AC:

AN:

4468

European-Finnish (FIN)

AF:

0.000776

AC:

AN:

9016

Middle Eastern (MID)

AF:

0.0104

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.00138

AC:

AN:

64452

Other (OTH)

AF:

0.00839

AC:

AN:

1908

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

135

202

270

337

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000150

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Kindler syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-1.1

Mutation Taster

=100/0

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over