NM_004860.4:c.17C>G

Variant names:

• chr17-7614516-G-C
• rs1018623796
• NM_004860.4:c.17C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004860.4(FXR2):​c.17C>G​(p.Ser6Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000147 in 1,358,626 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S6F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: FXR2 NM_004860.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.70
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15684491).

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.17C>G	p.Ser6Cys	missense	Exon 1 of 17	NP_004851.2	P51116
	SHBG	NM_001289114.2		c.-62+405G>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.17C>G	p.Ser6Cys	missense	Exon 1 of 17	ENSP00000250113.7	P51116
	SHBG	ENST00000575314.5	TSL:1	c.-62+405G>C		intron	N/A	ENSP00000458559.1	I3L145
	SHBG	ENST00000572262.5	TSL:1	c.-62+405G>C		intron	N/A	ENSP00000459999.1	I3L2X4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000147 AC: 2 AN: 1358626 Hom.: 0 Cov.: 30 AF XY: 0.00000149 AC XY: 1 AN XY: 669576

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000351 AC: 1 AN: 28478

American (AMR) AF: 0.00 AC: 0 AN: 32482

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24190

East Asian (EAS) AF: 0.00 AC: 0 AN: 31626

South Asian (SAS) AF: 0.00 AC: 0 AN: 75366

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39966

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5488

European-Non Finnish (NFE) AF: 9.39e-7 AC: 1 AN: 1064860

Other (OTH) AF: 0.00 AC: 0 AN: 56170

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0385499), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.086	T
Eigen	Benign	-0.059
Eigen_PC	Benign	0.047
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.55	T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		3.7
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	0.050	N
REVEL	Benign	0.036
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.016	D
Polyphen		0.21	B
Vest4		0.12
MutPred		0.25		Loss of disorder (P = 0.0098)
MVP		0.43
MPC		1.0
ClinPred		0.60	D
GERP RS		4.4
PromoterAI		0.059	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.19
gMVP		0.36

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: rs1018623796; hg19: chr17-7517834;