X-132077907-T-C

Variant names:

• chrX-132077907-T-C
• rs1428181347
• NM_194277.3:c.2110A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_194277.3(FRMD7):​c.2110A>G​(p.Thr704Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,208,235 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T704T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: FRMD7 NM_194277.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.57
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36516836).

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.2110A>G	p.Thr704Ala	missense	Exon 12 of 12	NP_919253.1	Q6ZUT3-1
	FRMD7	NM_001306193.2		c.2065A>G	p.Thr689Ala	missense	Exon 12 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.2110A>G	p.Thr704Ala	missense	Exon 12 of 12	ENSP00000298542.3	Q6ZUT3-1
	FRMD7	ENST00000464296.1	TSL:1	c.2065A>G	p.Thr689Ala	missense	Exon 12 of 12	ENSP00000417996.1	Q6ZUT3-2
	FRMD7	ENST00000370879.5	TSL:1	c.1750A>G	p.Thr584Ala	missense	Exon 8 of 8	ENSP00000359916.1	X6R7S7

Frequencies

GnomAD3 genomes AF: 0.00000889 AC: 1 AN: 112437 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

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: 0.0000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000547 AC: 1 AN: 182832 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: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000183 AC: 2 AN: 1095798 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 361250

African (AFR) AF: 0.00 AC: 0 AN: 26363

American (AMR) AF: 0.00 AC: 0 AN: 35195

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19367

East Asian (EAS) AF: 0.00 AC: 0 AN: 30182

South Asian (SAS) AF: 0.00 AC: 0 AN: 54075

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40522

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4129

European-Non Finnish (NFE) AF: 0.00000238 AC: 2 AN: 839961

Other (OTH) AF: 0.00 AC: 0 AN: 46004

GnomAD4 genome AF: 0.00000889 AC: 1 AN: 112437 Hom.: 0 Cov.: 23 AF XY: 0.0000289 AC XY: 1 AN XY: 34589

African (AFR) AF: 0.00 AC: 0 AN: 30932

American (AMR) AF: 0.00 AC: 0 AN: 10636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2648

East Asian (EAS) AF: 0.00 AC: 0 AN: 3595

South Asian (SAS) AF: 0.00 AC: 0 AN: 2726

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6153

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53304

Other (OTH) AF: 0.00 AC: 0 AN: 1516

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Uncertain	0.074	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.016	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.67	T
M_CAP	Pathogenic	0.67	D
MetaRNN	Benign	0.37	T
MetaSVM	Uncertain	-0.013	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		3.6
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.49
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.24	T
Polyphen		0.70	P
Vest4		0.22
MutPred		0.22		Gain of helix (P = 0.0164)
MVP		0.88
MPC		0.85
ClinPred		0.65	D
GERP RS		5.7
Varity_R		0.15
gMVP		0.28
Mutation Taster		=89/11	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: rs1428181347; hg19: chrX-131211935;