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

FERMT1 links:

Genome browser will be placed here

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FERMT1	NM_017671.5 link	c.1198T>C	p.Ser400Pro	missense_variant	Exon 10 of 15	ENST00000217289.9	NP_060141.3	Q9BQL6-1Q54A15Q49AC8
FERMT1	XM_024451935.2 link	c.1198T>C	p.Ser400Pro	missense_variant	Exon 10 of 15		XP_024307703.1
FERMT1	XM_047440259.1 link	c.1198T>C	p.Ser400Pro	missense_variant	Exon 10 of 15		XP_047296215.1
FERMT1	XM_047440260.1 link	c.913T>C	p.Ser305Pro	missense_variant	Exon 9 of 14		XP_047296216.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FERMT1	ENST00000217289.9 link	c.1198T>C	p.Ser400Pro	missense_variant	Exon 10 of 15	1	NM_017671.5	ENSP00000217289.4		Q9BQL6-1

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

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Kindler syndrome

Pathogenic:1

Feb 08, 2010

Biomedical Innovation Departament, CIEMAT

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

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

D;.

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.88

D;D

M_CAP

Pathogenic

0.62

MetaRNN

Pathogenic

0.90

D;D

MetaSVM

Pathogenic

0.88

MutationAssessor

Uncertain

2.7

M;.

PhyloP100

4.4

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-2.3

N;N

REVEL

Pathogenic

0.81

Sift

Benign

0.20

T;T

Sift4G

Benign

0.20

T;T

Polyphen

0.72

P;.

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over