chr17-7614519-G-A

Variant names:

• chr17-7614519-G-A
• rs966072827
• NM_004860.4:c.14C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_004860.4(FXR2):​c.14C>T​(p.Ala5Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000601 in 1,498,296 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 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000059 (0 hom.)
• 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.26909852).
• BS2: High AC in GnomAdExome4 at 8 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.14C>T	p.Ala5Val	missense	Exon 1 of 17	NP_004851.2	P51116
	SHBG	NM_001289114.2		c.-62+408G>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.14C>T	p.Ala5Val	missense	Exon 1 of 17	ENSP00000250113.7	P51116
	SHBG	ENST00000575314.5	TSL:1	c.-62+408G>A		intron	N/A	ENSP00000458559.1	I3L145
	SHBG	ENST00000572262.5	TSL:1	c.-62+408G>A		intron	N/A	ENSP00000459999.1	I3L2X4

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151992 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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000594 AC: 8 AN: 1346304 Hom.: 0 Cov.: 30 AF XY: 0.00000453 AC XY: 3 AN XY: 662756

African (AFR) AF: 0.00 AC: 0 AN: 27756

American (AMR) AF: 0.00 AC: 0 AN: 30828

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23952

East Asian (EAS) AF: 0.00 AC: 0 AN: 30846

South Asian (SAS) AF: 0.00 AC: 0 AN: 74148

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39290

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5432

European-Non Finnish (NFE) AF: 0.00000661 AC: 7 AN: 1058390

Other (OTH) AF: 0.0000180 AC: 1 AN: 55662

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151992 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74234

African (AFR) AF: 0.00 AC: 0 AN: 41420

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5130

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67948

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

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	Uncertain	0.027	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.078	T
Eigen	Benign	0.11
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.63	T
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		3.4
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.058
Sift	Uncertain	0.013	D
Sift4G	Benign	0.21	T
Polyphen		0.88	P
Vest4		0.37
MutPred		0.16		Gain of sheet (P = 0.0221)
MVP		0.45
MPC		1.0
ClinPred		0.64	D
GERP RS		4.4
PromoterAI		-0.024	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.24
gMVP		0.23
Mutation Taster		=73/27	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: rs966072827; hg19: chr17-7517837;