17-7614523-G-C

Position:

chr17-7614523-G-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_004860.4(FXR2):c.10C>G(p.Leu4Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000523 in 1,339,486 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000052 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

FXR2
NM_004860.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.40

Variant links:

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]

FXR2 links:

SHBG (HGNC:10839): (sex hormone binding globulin) This gene encodes a steroid binding protein that was first described as a plasma protein secreted by the liver but is now thought to participate in the regulation of steroid responses. The encoded protein transports androgens and estrogens in the blood, binding each steroid molecule as a dimer formed from identical or nearly identical monomers. Polymorphisms in this gene have been associated with polycystic ovary syndrome and type 2 diabetes mellitus. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

SHBG links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.13666382).

BS2

High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
FXR2	NM_004860.4 linkuse as main transcript	c.10C>G	p.Leu4Val	missense_variant	1/17	ENST00000250113.12
FXR2	XM_047437106.1 linkuse as main transcript	c.10C>G	p.Leu4Val	missense_variant	1/17
SHBG	NM_001289114.2 linkuse as main transcript	c.-62+412G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FXR2	ENST00000250113.12 linkuse as main transcript	c.10C>G	p.Leu4Val	missense_variant	1/17	1	NM_004860.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

151960

Hom.:

Cov.:

FAILED QC

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000102

AC:

AN:

98428

Hom.:

AF XY:

0.0000178

AC XY:

AN XY:

56210

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000364

GnomAD4 exome

AF:

0.00000523

AC:

AN:

1339486

Hom.:

Cov.:

AF XY:

0.00000759

AC XY:

AN XY:

659070

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000328

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000474

Gnomad4 OTH exome

AF:

0.0000181

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

151960

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74212

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 06, 2022

The c.10C>G (p.L4V) alteration is located in exon 1 (coding exon 1) of the FXR2 gene. This alteration results from a C to G substitution at nucleotide position 10, causing the leucine (L) at amino acid position 4 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

0.062

BayesDel_addAF

Benign

-0.075

BayesDel_noAF

Benign

-0.35

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.085

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.084

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.58

M_CAP

Pathogenic

0.30

MetaRNN

Benign

0.14

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

MutationTaster

Benign

0.67

D;D;D;D;D;D;D;D

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.14

REVEL

Benign

0.025

Sift

Benign

0.033

Sift4G

Benign

0.48

Polyphen

0.21

Vest4

0.17

MutPred

0.16

Gain of sheet (P = 0.0344);

MVP

0.31

MPC

1.1

ClinPred

0.30

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.20

gMVP

0.17

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over