chr17-7614516-G-A

Variant names:

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

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.17C>T​(p.Ser6Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000118 in 1,358,628 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: not found (cov: 31)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: FXR2 NM_004860.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16528738).
• BS2: High AC in GnomAdExome4 at 16 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.17C>T	p.Ser6Phe	missense	Exon 1 of 17	NP_004851.2	P51116
	SHBG	NM_001289114.2		c.-62+405G>A		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>T	p.Ser6Phe	missense	Exon 1 of 17	ENSP00000250113.7	P51116
	SHBG	ENST00000575314.5	TSL:1	c.-62+405G>A		intron	N/A	ENSP00000458559.1	I3L145
	SHBG	ENST00000572262.5	TSL:1	c.-62+405G>A		intron	N/A	ENSP00000459999.1	I3L2X4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000862 AC: 1 AN: 116058 AF XY: 0.0000153

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: 0.000313

GnomAD4 exome AF: 0.0000118 AC: 16 AN: 1358628 Hom.: 0 Cov.: 30 AF XY: 0.0000164 AC XY: 11 AN XY: 669578

African (AFR) AF: 0.00 AC: 0 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: 0.0000122 AC: 13 AN: 1064862

Other (OTH) AF: 0.0000534 AC: 3 AN: 56170

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000435 Hom.: 0

Bravo AF: 0.0000151

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	0.14
BayesDel_addAF	Benign	-0.0034	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.028
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.65	T
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		3.7
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.49	N
REVEL	Benign	0.024
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.072	B
Vest4		0.20
MutPred		0.24		Loss of glycosylation at S6 (P = 0.0153)
MVP		0.44
MPC		1.1
ClinPred		0.41	T
GERP RS		4.4
PromoterAI		0.045	Neutral
Varity_R		0.29
gMVP		0.33
Mutation Taster		=95/5	polymorphism

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;