X-132077924-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_194277.3(FRMD7):c.2093C>T(p.Pro698Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000331 in 1,208,664 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000018 ( 0 hom. 0 hem. )

Consequence

FRMD7
NM_194277.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.48

Variant links:

Genes affected

FRMD7 (HGNC:8079): (FERM domain containing 7) Predicted to enable guanyl-nucleotide exchange factor activity. Predicted to be involved in regulation of neuron projection development. Predicted to act upstream of or within several processes, including negative regulation of stress fiber assembly; positive regulation of lamellipodium assembly; and positive regulation of small GTPase mediated signal transduction. Located in cytosol; nucleoplasm; and plasma membrane. Implicated in congenital nystagmus 1. [provided by Alliance of Genome Resources, Apr 2022]

FRMD7 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.14876446).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FRMD7	NM_194277.3 linkuse as main transcript	c.2093C>T	p.Pro698Leu	missense_variant	12/12	ENST00000298542.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FRMD7	ENST00000298542.9 linkuse as main transcript	c.2093C>T	p.Pro698Leu	missense_variant	12/12	1	NM_194277.3	P1	Q6ZUT3-1
FRMD7	ENST00000464296.1 linkuse as main transcript	c.2048C>T	p.Pro683Leu	missense_variant	12/12	1			Q6ZUT3-2
FRMD7	ENST00000370879.5 linkuse as main transcript	c.1733C>T	p.Pro578Leu	missense_variant	8/8	1

Frequencies

GnomAD3 genomes

AF:

0.0000178

AC:

AN:

112049

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34223

show subpopulations

Gnomad AFR

AF:

0.0000324

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000661

GnomAD3 exomes

AF:

0.00000547

AC:

AN:

182789

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67495

show subpopulations

Gnomad AFR exome

AF:

0.0000760

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000182

AC:

AN:

1096615

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

362029

show subpopulations

Gnomad4 AFR exome

AF:

0.0000758

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000178

AC:

AN:

112049

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34223

show subpopulations

Gnomad4 AFR

AF:

0.0000324

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000661

Bravo

AF:

0.0000416

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 30, 2022

This variant has not been reported in the literature in individuals affected with FRMD7-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 1003402). This variant is present in population databases (no rsID available, gnomAD 0.008%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 698 of the FRMD7 protein (p.Pro698Leu). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.38

Cadd

Benign

9.5

Dann

Benign

0.92

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.65

T;T;T

M_CAP

Pathogenic

0.54

MetaRNN

Benign

0.15

T;T;T

MetaSVM

Benign

-0.74

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.40

N;N;N

REVEL

Benign

0.12

Sift

Uncertain

0.0020

D;D;D

Sift4G

Benign

0.38

T;T;T

Polyphen

0.039, 0.0010

.;B;B

Vest4

0.050

MutPred

0.26

.;Loss of loop (P = 0.0073);.;

MVP

0.55

MPC

0.28

ClinPred

0.099

GERP RS

3.8

Varity_R

0.082

gMVP

0.16

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over