15-43883778-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3 PP5

The NM_032892.5(FRMD5):c.1060T>C(p.Ser354Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FRMD5 NM_032892.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.60

Genes affected

FRMD5 (HGNC:28214): (FERM domain containing 5) Enables integrin binding activity and protein kinase binding activity. Involved in negative regulation of cell motility; positive regulation of cell adhesion; and regulation of cell migration. Located in adherens junction. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_032892.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.759
• PP5: Variant 15-43883778-A-G is Pathogenic according to our data. Variant chr15-43883778-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 1712504.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-43883778-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FRMD5	NM_032892.5	c.1060T>C	p.Ser354Pro	missense_variant	13/14	ENST00000417257.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FRMD5	ENST00000417257.6	c.1060T>C	p.Ser354Pro	missense_variant	13/14	1	NM_032892.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Neurodevelopmental disorder with eye movement abnormalities and ataxia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 27, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Benign	0.13	T;T;T;.;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D;D
M_CAP	Uncertain	0.090	D
MetaRNN	Pathogenic	0.76	D;D;D;D;D
MetaSVM	Uncertain	0.19	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.81	D
Sift4G	Uncertain	0.013	D;D;D;T;D
Polyphen		0.90, 0.97	.;P;D;.;.
Vest4		0.59
MutPred		0.41		.;Loss of phosphorylation at S354 (P = 0.0297);Loss of phosphorylation at S354 (P = 0.0297);.;.;
MVP		0.93
MPC		1.9
ClinPred		0.90	D
GERP RS		5.5
Varity_R		0.46
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-44175976;