X-132084540-A-T

Variant names:

• chrX-132084540-A-T
• rs387906720
• NM_194277.3:c.691T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP3

The NM_194277.3(FRMD7):​c.691T>A​(p.Leu231Met) 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 pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L231V) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.3e-7 (0 hom. 1 hem.)
  • Failed GnomAD Quality Control
• Consequence: FRMD7 NM_194277.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.87
• Publications: 5 publications found

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)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_194277.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-132084540-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 29976.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.828

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.691T>A	p.Leu231Met	missense	Exon 8 of 12	NP_919253.1	Q6ZUT3-1
	FRMD7	NM_001306193.2		c.646T>A	p.Leu216Met	missense	Exon 8 of 12	NP_001293122.1	Q6ZUT3-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRMD7	ENST00000298542.9	TSL:1 MANE Select	c.691T>A	p.Leu231Met	missense	Exon 8 of 12	ENSP00000298542.3	Q6ZUT3-1
	FRMD7	ENST00000464296.1	TSL:1	c.646T>A	p.Leu216Met	missense	Exon 8 of 12	ENSP00000417996.1	Q6ZUT3-2
	FRMD7	ENST00000370879.5	TSL:1	c.331T>A	p.Leu111Met	missense	Exon 4 of 8	ENSP00000359916.1	X6R7S7

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD2 exomes AF: 0.00000546 AC: 1 AN: 183182 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.31e-7 AC: 1 AN: 1074584 Hom.: 0 Cov.: 25 AF XY: 0.00000292 AC XY: 1 AN XY: 343008

African (AFR) AF: 0.00 AC: 0 AN: 25983

American (AMR) AF: 0.00 AC: 0 AN: 35180

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19251

East Asian (EAS) AF: 0.00 AC: 0 AN: 30110

South Asian (SAS) AF: 0.00 AC: 0 AN: 53590

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40526

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4067

European-Non Finnish (NFE) AF: 0.00000122 AC: 1 AN: 820545

Other (OTH) AF: 0.00 AC: 0 AN: 45332

GnomAD4 genome Cov.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		2.9
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.7	N
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.72
MutPred		0.76		Gain of methylation at K234 (P = 0.0544)
MVP		0.95
MPC		0.85
ClinPred		0.95	D
GERP RS		0.43
Varity_R		0.89
gMVP		0.64
Mutation Taster		=84/16	polymorphism

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

Other links and lift over

dbSNP: rs387906720; hg19: chrX-131218568;