15-43883787-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PS1_Moderate PM1 PM2 PM5 PP5

The NM_032892.5(FRMD5):c.1051A>G(p.Ser351Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S351N) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FRMD5 NM_032892.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.38

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 9 ACMG points.

• PS1: Transcript NM_032892.5 (FRMD5) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_032892.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-43883786-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2501687.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP5: Variant 15-43883787-T-C is Pathogenic according to our data. Variant chr15-43883787-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 1712501.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-43883787-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FRMD5	NM_032892.5	c.1051A>G	p.Ser351Gly	missense_variant	13/14	ENST00000417257.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FRMD5	ENST00000417257.6	c.1051A>G	p.Ser351Gly	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	0.67
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	-0.010
Cadd	Uncertain	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.12	T;T;T;.;.
Eigen	Benign	0.065
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D;D;D
M_CAP	Benign	0.061	D
MetaRNN	Uncertain	0.56	D;D;D;D;D
MetaSVM	Uncertain	-0.27	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.72	T
Sift4G	Benign	0.075	T;T;T;T;T
Polyphen		0.0070, 0.012	.;B;B;.;.
Vest4		0.55
MutPred		0.41		.;Loss of phosphorylation at S351 (P = 0.0225);Loss of phosphorylation at S351 (P = 0.0225);.;.;
MVP		0.94
MPC		0.78
ClinPred		0.93	D
GERP RS		5.5
Varity_R		0.36
gMVP		0.69

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: chr15-44175985;