17-7592525-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_004860.4(FXR2):c.1804A>G(p.Ile602Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,613,964 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: FXR2 NM_004860.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0330

Genes affected

FXR2 (HGNC:4024): (FMR1 autosomal homolog 2) The protein encoded by this gene is a RNA binding protein containing two KH domains and one RCG box, which is similar to FMRP and FXR1. It associates with polyribosomes, predominantly with 60S large ribosomal subunits. This encoded protein may self-associate or interact with FMRP and FXR1. It may have a role in the development of fragile X cognitive disability syndrome. [provided by RefSeq, Jul 2008]

MPDU1 (HGNC:7207): (mannose-P-dolichol utilization defect 1) This gene encodes an endoplasmic reticulum membrane protein that is required for utilization of the mannose donor mannose-P-dolichol in the synthesis of lipid-linked oligosaccharides and glycosylphosphatidylinositols. Mutations in this gene result in congenital disorder of glycosylation type If. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2008]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009209782).
• BS2: High AC in GnomAdExome at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FXR2	NM_004860.4	c.1804A>G	p.Ile602Val	missense_variant	15/17	ENST00000250113.12
FXR2	XM_047437106.1	c.1804A>G	p.Ile602Val	missense_variant	15/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FXR2	ENST00000250113.12	c.1804A>G	p.Ile602Val	missense_variant	15/17	1	NM_004860.4	P1
FXR2	ENST00000704984.1	c.2023A>G	p.Ile675Val	missense_variant	15/17
MPDU1	ENST00000423172.6	c.*53T>C		3_prime_UTR_variant	6/6	2
MPDU1	ENST00000584378.5			downstream_gene_variant		4

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000883 AC: 22 AN: 249258 Hom.: 0 AF XY: 0.0000740 AC XY: 10 AN XY: 135218

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00122

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: 0.0000157 AC: 23 AN: 1461648 Hom.: 0 Cov.: 32 AF XY: 0.0000193 AC XY: 14 AN XY: 727114

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000504

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152316 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74484

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ExAC AF: 0.0000661 AC: 8

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

Jun 29, 2023

The c.1804A>G (p.I602V) alteration is located in exon 15 (coding exon 15) of the FXR2 gene. This alteration results from a A to G substitution at nucleotide position 1804, causing the isoleucine (I) at amino acid position 602 to be replaced by a valine (V). 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	0.067
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	7.7
Dann	Benign	0.68
DEOGEN2	Benign	0.096	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.0092	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	0.99	D;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.020	N
REVEL	Benign	0.062
Sift	Benign	0.14	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.15
MutPred		0.073		Loss of catalytic residue at I602 (P = 0.0892);
MVP		0.15
MPC		0.24
ClinPred		0.021	T
GERP RS		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.020
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs554393214; hg19: chr17-7495843;