20-6089031-A-G

Position:

• chr20-6089031-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_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
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.37

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 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 id is 224165.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr20-6089031-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FERMT1	NM_017671.5	c.1198T>C	p.Ser400Pro	missense_variant	10/15	ENST00000217289.9	NP_060141.3
FERMT1	XM_024451935.2	c.1198T>C	p.Ser400Pro	missense_variant	10/15		XP_024307703.1
FERMT1	XM_047440259.1	c.1198T>C	p.Ser400Pro	missense_variant	10/15		XP_047296215.1
FERMT1	XM_047440260.1	c.913T>C	p.Ser305Pro	missense_variant	9/14		XP_047296216.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FERMT1	ENST00000217289.9	c.1198T>C	p.Ser400Pro	missense_variant	10/15	1	NM_017671.5	ENSP00000217289.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459592 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726174

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Kindler syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Biomedical Innovation Departament, CIEMAT

Feb 08, 2010

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Uncertain	2.7	M;.
PrimateAI	Uncertain	0.53	T
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	D
GERP RS		5.8
Varity_R		0.68
gMVP		0.84

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

LitVar

Other links and lift over

dbSNP: rs869312718; hg19: chr20-6069678;