14-51704916-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001267046.2(FRMD6):c.539A>G(p.Glu180Gly) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FRMD6 NM_001267046.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.14

Genes affected

FRMD6 (HGNC:19839): (FERM domain containing 6) Predicted to be involved in actomyosin structure organization. Predicted to act upstream of or within apical constriction; cellular protein localization; and regulation of actin filament-based process. Predicted to be located in apical junction complex. Predicted to be active in cytoskeleton. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.801

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FRMD6	NM_001267046.2	c.539A>G	p.Glu180Gly	missense_variant	6/14	ENST00000344768.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FRMD6	ENST00000344768.10	c.539A>G	p.Glu180Gly	missense_variant	6/14	2	NM_001267046.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 04, 2024

The c.515A>G (p.E172G) alteration is located in exon 7 (coding exon 5) of the FRMD6 gene. This alteration results from a A to G substitution at nucleotide position 515, causing the glutamic acid (E) at amino acid position 172 to be replaced by a glycine (G). 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	0.17
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
Cadd	Pathogenic	26
Dann	Uncertain	1.0
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.097	D
MetaRNN	Pathogenic	0.80	D;D;D;D;D;D
MetaSVM	Uncertain	-0.17	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.6	D;D;D;D;D;D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.025	D;D;D;D;D;D
Sift4G	Uncertain	0.029	D;D;D;D;D;D
Polyphen		0.13	B;B;B;.;B;.
Vest4		0.69
MutPred		0.46		.;.;Loss of ubiquitination at K175 (P = 0.0431);.;.;.;
MVP		0.82
MPC		0.29
ClinPred		0.98	D
GERP RS		5.6
Varity_R		0.31
gMVP		0.66

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: chr14-52171634;