dbSNP rs786205896: FRMD7:p.Met186Val (chrX-132085670-T-C) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate

The NM_194277.3(FRMD7):c.556A>G(p.Met186Val) variant causes a missense change. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M186T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 23)

Consequence

FRMD7
NM_194277.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 6.24

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

nystagmus 1, congenital, X-linked
Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

FRMD7 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_194277.3

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.947

PP5

Variant X-132085670-T-C is Pathogenic according to our data. Variant chrX-132085670-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 192295.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_194277.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRMD7	NM_194277.3	MANE Select	c.556A>G	p.Met186Val	missense	Exon 7 of 12	NP_919253.1	Q6ZUT3-1
	FRMD7	NM_001306193.2		c.511A>G	p.Met171Val	missense	Exon 7 of 12	NP_001293122.1	Q6ZUT3-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FRMD7	ENST00000298542.9	TSL:1 MANE Select	c.556A>G	p.Met186Val	missense	Exon 7 of 12	ENSP00000298542.3	Q6ZUT3-1
FRMD7	ENST00000464296.1	TSL:1	c.511A>G	p.Met171Val	missense	Exon 7 of 12	ENSP00000417996.1	Q6ZUT3-2
FRMD7	ENST00000370879.5	TSL:1	c.196A>G	p.Met66Val	missense	Exon 3 of 8	ENSP00000359916.1	X6R7S7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Nystagmus 1, congenital, X-linked (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.23

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.70

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.79

M_CAP

Pathogenic

0.73

MetaRNN

Pathogenic

0.95

MetaSVM

Uncertain

0.61

MutationAssessor

Pathogenic

3.5

PhyloP100

6.2

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-3.6

REVEL

Pathogenic

0.80

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.010

Polyphen

0.96

Vest4

0.89

MutPred

0.69

Loss of sheet (P = 0.0817)

MVP

0.95

MPC

0.86

ClinPred

0.98

GERP RS

5.7

Varity_R

0.96

gMVP

0.85

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over