17-7591901-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_004860.4(FXR2):c.1951A>G(p.Lys651Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0026 in 1,601,496 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (11 hom.)
• Consequence: FXR2 NM_004860.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.49

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0082268715).
• BP6: Variant 17-7591901-T-C is Benign according to our data. Variant chr17-7591901-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 786838.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-7591901-T-C is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 311 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FXR2	NM_004860.4	c.1951A>G	p.Lys651Glu	missense_variant	17/17	ENST00000250113.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FXR2	ENST00000250113.12	c.1951A>G	p.Lys651Glu	missense_variant	17/17	1	NM_004860.4	P1

Frequencies

GnomAD3 genomes AF: 0.00204 AC: 311 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00169

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00338

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00239 AC: 587 AN: 245142 Hom.: 2 AF XY: 0.00232 AC XY: 309 AN XY: 133358

Gnomad AFR exome AF: 0.000326

Gnomad AMR exome AF: 0.00253

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000721

Gnomad FIN exome AF: 0.00112

Gnomad NFE exome AF: 0.00394

Gnomad OTH exome AF: 0.00284

GnomAD4 exome AF: 0.00266 AC: 3850 AN: 1449222 Hom.: 11 Cov.: 27 AF XY: 0.00256 AC XY: 1851 AN XY: 721812

Gnomad4 AFR exome AF: 0.000451

Gnomad4 AMR exome AF: 0.00231

Gnomad4 ASJ exome AF: 0.0000770

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000942

Gnomad4 FIN exome AF: 0.00139

Gnomad4 NFE exome AF: 0.00314

Gnomad4 OTH exome AF: 0.00192

GnomAD4 genome AF: 0.00202 AC: 308 AN: 152274 Hom.: 0 Cov.: 32 AF XY: 0.00183 AC XY: 136 AN XY: 74460

Gnomad4 AFR AF: 0.000650

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00169

Gnomad4 NFE AF: 0.00338

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00264 Hom.: 1

Bravo AF: 0.00201

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.00107 AC: 4

ESP6500EA AF: 0.00269 AC: 22

ExAC AF: 0.00298 AC: 360

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00256

EpiControl AF: 0.00255

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jul 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.081	T
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.0082	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	D;N
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.14
Sift	Uncertain	0.014	D
Sift4G	Benign	1.0	T
Polyphen		0.88	P
Vest4		0.28
MVP		0.56
MPC		0.46
ClinPred		0.030	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.21
gMVP		0.21

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

Other links and lift over

dbSNP: rs190521854; hg19: chr17-7495219;