Genetic Variant NM_017671.5:c.1198T>C (chr20-6089031-A-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_ModeratePP5_Moderate

The NM_017671.5(FERMT1):c.1198T>C(p.Ser400Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,459,592 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

FERMT1
NM_017671.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 4.37

Publications

4 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.903

PP5

Variant 20-6089031-A-G is Pathogenic according to our data. Variant chr20-6089031-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 224165.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1198T>C	p.Ser400Pro	missense	Exon 10 of 15	NP_060141.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FERMT1	ENST00000217289.9	TSL:1 MANE Select	c.1198T>C	p.Ser400Pro	missense	Exon 10 of 15	ENSP00000217289.4	Q9BQL6-1
FERMT1	ENST00000478194.1	TSL:1	n.158T>C		non_coding_transcript_exon	Exon 2 of 7
FERMT1	ENST00000536936.1	TSL:1	n.*700T>C		non_coding_transcript_exon	Exon 9 of 14	ENSP00000441063.2	G3V1L6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1459592

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726174

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33426

American (AMR)

AF:

0.00

AC:

AN:

44672

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26052

East Asian (EAS)

AF:

0.00

AC:

AN:

39668

South Asian (SAS)

AF:

0.00

AC:

AN:

86216

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53342

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1110174

Other (OTH)

AF:

0.00

AC:

AN:

60282

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Pathogenic

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

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.42

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.62

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.88

M_CAP

Pathogenic

0.62

MetaRNN

Pathogenic

0.90

MetaSVM

Pathogenic

0.88

MutationAssessor

Uncertain

2.7

PhyloP100

4.4

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-2.3

REVEL

Pathogenic

0.81

Sift

Benign

0.20

Sift4G

Benign

0.20

Polyphen

0.72

Vest4

0.89

MutPred

0.62

Loss of MoRF binding (P = 0.0685)

MVP

0.94

MPC

0.68

ClinPred

0.94

GERP RS

5.8

Varity_R

0.68

gMVP

0.84

Mutation Taster

=24/76

disease causing (ClinVar)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over