17-49041434-T-C

Position:

• chr17-49041434-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_006546.4(IGF2BP1):​c.875T>C​(p.Ile292Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: IGF2BP1 NM_006546.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.99

Genes affected

IGF2BP1 (HGNC:28866): (insulin like growth factor 2 mRNA binding protein 1) This gene encodes a member of the insulin-like growth factor 2 mRNA-binding protein family. The protein encoded by this gene contains four K homology domains and two RNA recognition motifs. It functions by binding to the mRNAs of certain genes, including insulin-like growth factor 2, beta-actin and beta-transducin repeat-containing protein, and regulating their translation. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2009]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.948

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGF2BP1	NM_006546.4	c.875T>C	p.Ile292Thr	missense_variant	8/15	ENST00000290341.8	NP_006537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGF2BP1	ENST00000290341.8	c.875T>C	p.Ile292Thr	missense_variant	8/15	1	NM_006546.4	ENSP00000290341.3
IGF2BP1	ENST00000431824.2	c.458T>C	p.Ile153Thr	missense_variant	6/13	1		ENSP00000389135.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 09, 2022

The c.875T>C (p.I292T) alteration is located in exon 8 (coding exon 8) of the IGF2BP1 gene. This alteration results from a T to C substitution at nucleotide position 875, causing the isoleucine (I) at amino acid position 292 to be replaced by a threonine (T). 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	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Uncertain	-0.028	T
MutationAssessor	Uncertain	2.8	M;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-4.9	D;D
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.062	T;T
Polyphen		0.96	D;.
Vest4		0.92
MutPred		0.84		Loss of stability (P = 0.0112);.;
MVP		0.92
MPC		1.5
ClinPred		0.99	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.88
gMVP		0.99

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-47118796;