20-6084063-A-T

Position:

• chr20-6084063-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_017671.5(FERMT1):​c.1695T>A​(p.Phe565Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F565F) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FERMT1 NM_017671.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.118

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]

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, 0.981

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FERMT1	NM_017671.5	c.1695T>A	p.Phe565Leu	missense_variant	13/15	ENST00000217289.9	NP_060141.3
FERMT1	XM_024451935.2	c.1695T>A	p.Phe565Leu	missense_variant	13/15		XP_024307703.1
FERMT1	XM_047440259.1	c.1695T>A	p.Phe565Leu	missense_variant	13/15		XP_047296215.1
FERMT1	XM_047440260.1	c.1410T>A	p.Phe470Leu	missense_variant	12/14		XP_047296216.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FERMT1	ENST00000217289.9	c.1695T>A	p.Phe565Leu	missense_variant	13/15	1	NM_017671.5	ENSP00000217289	P1
FERMT1	ENST00000478194.1	n.655T>A		non_coding_transcript_exon_variant	5/7	1
FERMT1	ENST00000536936.1	c.*1197T>A		3_prime_UTR_variant, NMD_transcript_variant	12/14	1		ENSP00000441063
FERMT1	ENST00000699095.1	c.1695T>A	p.Phe565Leu	missense_variant	12/14			ENSP00000514127	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 41

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D;.
Eigen	Benign	-0.0042
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Pathogenic	3.1	M;.
MutationTaster	Benign	9.6e-7	P;P
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.3	D;D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0060	D;D
Sift4G	Uncertain	0.013	D;D
Polyphen		0.99	D;.
Vest4		0.85
MutPred		0.85		Gain of catalytic residue at F565 (P = 0.0448);.;
MVP		0.87
MPC		0.92
ClinPred		1.0	D
GERP RS		-2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.67
gMVP		0.79

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: rs753927; hg19: chr20-6064710;