7-23312812-C-T

Variant names:

• chr7-23312812-C-T
• rs145056288
• NM_006547.3:c.1564G>A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_006547.3(IGF2BP3):​c.1564G>A​(p.Val522Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000768 in 1,612,368 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00057 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00079 (2 hom.)
• Consequence: IGF2BP3 NM_006547.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.12

Genes affected

IGF2BP3 (HGNC:28868): (insulin like growth factor 2 mRNA binding protein 3) The protein encoded by this gene is primarily found in the nucleolus, where it can bind to the 5' UTR of the insulin-like growth factor II leader 3 mRNA and may repress translation of insulin-like growth factor II during late development. The encoded protein contains several KH domains, which are important in RNA binding and are known to be involved in RNA synthesis and metabolism. A pseudogene exists on chromosome 7, and there are putative pseudogenes on other chromosomes. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.022533685).
• BS2: High Homozygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGF2BP3	NM_006547.3	c.1564G>A	p.Val522Ile	missense_variant	Exon 14 of 15	ENST00000258729.8	NP_006538.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGF2BP3	ENST00000258729.8	c.1564G>A	p.Val522Ile	missense_variant	Exon 14 of 15	1	NM_006547.3	ENSP00000258729.3

Frequencies

GnomAD3 genomes AF: 0.000572 AC: 87 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000897

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000693 AC: 173 AN: 249542 Hom.: 1 AF XY: 0.000623 AC XY: 84 AN XY: 134864

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000559

Gnomad ASJ exome AF: 0.00359

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.000936

Gnomad OTH exome AF: 0.000819

GnomAD4 exome AF: 0.000789 AC: 1152 AN: 1460030 Hom.: 2 Cov.: 30 AF XY: 0.000723 AC XY: 525 AN XY: 726300

Gnomad4 AFR exome AF: 0.000210

Gnomad4 AMR exome AF: 0.000543

Gnomad4 ASJ exome AF: 0.00322

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000169

Gnomad4 NFE exome AF: 0.000848

Gnomad4 OTH exome AF: 0.00134

GnomAD4 genome AF: 0.000571 AC: 87 AN: 152338 Hom.: 0 Cov.: 32 AF XY: 0.000631 AC XY: 47 AN XY: 74484

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000897

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000292 Hom.: 0

Bravo AF: 0.000684

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000642 AC: 78

EpiCase AF: 0.000872

EpiControl AF: 0.000949

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 14, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1564G>A (p.V522I) alteration is located in exon 14 (coding exon 14) of the IGF2BP3 gene. This alteration results from a G to A substitution at nucleotide position 1564, causing the valine (V) at amino acid position 522 to be replaced by an isoleucine (I). 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	0.10
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	22
DANN	Benign	0.94
DEOGEN2	Benign	0.031	T;.
Eigen	Benign	0.029
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.023	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.22	N;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.35	N;.
REVEL	Benign	0.12
Sift	Benign	0.57	T;.
Sift4G	Benign	0.23	T;T
Polyphen		0.025	B;.
Vest4		0.56
MVP		0.33
MPC		0.67
ClinPred		0.017	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.086
gMVP		0.28

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

Publications

LitVar

Other links and lift over

dbSNP: rs145056288; hg19: chr7-23352431;