15-43874219-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032892.5(FRMD5):c.1379A>T(p.Lys460Met) 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 benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FRMD5 NM_032892.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.52

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20610777).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FRMD5	NM_032892.5	c.1379A>T	p.Lys460Met	missense_variant	14/14	ENST00000417257.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FRMD5	ENST00000417257.6	c.1379A>T	p.Lys460Met	missense_variant	14/14	1	NM_032892.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 07, 2022

The c.1379A>T (p.K460M) alteration is located in exon 14 (coding exon 14) of the FRMD5 gene. This alteration results from a A to T substitution at nucleotide position 1379, causing the lysine (K) at amino acid position 460 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.071	D
BayesDel_noAF	Benign	-0.14
Cadd	Benign	22
Dann	Uncertain	0.98
DEOGEN2	Benign	0.012	T;T;T;.;.;T
Eigen	Benign	-0.092
Eigen_PC	Benign	0.053
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.92	D;D;D;D;D;D
M_CAP	Uncertain	0.088	D
MetaRNN	Benign	0.21	T;T;T;T;T;T
MetaSVM	Benign	-0.30	T
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.67	T
Sift4G	Benign	0.13	T;T;T;T;T;.
Polyphen		0.031, 0.028	.;B;B;.;.;.
Vest4		0.18
MutPred		0.33		.;Loss of ubiquitination at K460 (P = 0.0017);Loss of ubiquitination at K460 (P = 0.0017);.;.;.;
MVP		0.45
MPC		0.082
ClinPred		0.26	T
GERP RS		4.6
Varity_R		0.085
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr15-44166417;