rs974541378

Variant names:

• chr17-7614523-G-C
• rs974541378
• NM_004860.4:c.10C>G

Your query was ambiguous. Multiple possible variants found:

• chr17-7614523-G-C
• chr17-7614523-G-A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.40
• Publications: 0 publications found

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]

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]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13666382).
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004860.4. 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
	FXR2	NM_004860.4	MANE Select	c.10C>G	p.Leu4Val	missense	Exon 1 of 17	NP_004851.2	P51116
	SHBG	NM_001289114.2		c.-62+412G>C		intron	N/A	NP_001276043.1	I3L145

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FXR2	ENST00000250113.12	TSL:1 MANE Select	c.10C>G	p.Leu4Val	missense	Exon 1 of 17	ENSP00000250113.7	P51116
	SHBG	ENST00000575314.5	TSL:1	c.-62+412G>C		intron	N/A	ENSP00000458559.1	I3L145
	SHBG	ENST00000572262.5	TSL:1	c.-62+412G>C		intron	N/A	ENSP00000459999.1	I3L2X4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 151960 Hom.: 0 Cov.: 31

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

GnomAD2 exomes AF: 0.0000102 AC: 1 AN: 98428 AF XY: 0.0000178

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: 0.00

Gnomad OTH exome AF: 0.000364

GnomAD4 exome AF: 0.00000523 AC: 7 AN: 1339486 Hom.: 0 Cov.: 30 AF XY: 0.00000759 AC XY: 5 AN XY: 659070

African (AFR) AF: 0.00 AC: 0 AN: 27416

American (AMR) AF: 0.00 AC: 0 AN: 29728

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23768

East Asian (EAS) AF: 0.0000328 AC: 1 AN: 30466

South Asian (SAS) AF: 0.00 AC: 0 AN: 73506

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5372

European-Non Finnish (NFE) AF: 0.00000474 AC: 5 AN: 1055266

Other (OTH) AF: 0.0000181 AC: 1 AN: 55376

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 151960 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74212

African (AFR) AF: 0.00 AC: 0 AN: 41408

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5114

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67950

Other (OTH) AF: 0.00 AC: 0 AN: 2090

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.085	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.084
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.58	T
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		3.4
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.025
Sift	Benign	0.033	D
Sift4G	Benign	0.48	T
Polyphen		0.21	B
Vest4		0.17
MutPred		0.16		Gain of sheet (P = 0.0344)
MVP		0.31
MPC		1.1
ClinPred		0.30	T
GERP RS		3.8
PromoterAI		-0.12	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.20
gMVP		0.17
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs974541378; hg19: chr17-7517841;