15-98911384-G-C

Variant names:

• chr15-98911384-G-C
• rs33958176
• NM_000875.5:c.1532G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000875.5(IGF1R):​c.1532G>C​(p.Arg511Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. R511Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IGF1R NM_000875.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.00
• Publications: 0 publications found

Genes affected

IGF1R (HGNC:5465): (insulin like growth factor 1 receptor) This receptor binds insulin-like growth factor with a high affinity. It has tyrosine kinase activity. The insulin-like growth factor I receptor plays a critical role in transformation events. Cleavage of the precursor generates alpha and beta subunits. It is highly overexpressed in most malignant tissues where it functions as an anti-apoptotic agent by enhancing cell survival. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, May 2014]

IGF1R Gene-Disease associations (from GenCC):

• growth delay due to insulin-like growth factor I resistance

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3850665).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGF1R	NM_000875.5	c.1532G>C	p.Arg511Pro	missense_variant	Exon 7 of 21	ENST00000650285.1	NP_000866.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGF1R	ENST00000650285.1	c.1532G>C	p.Arg511Pro	missense_variant	Exon 7 of 21		NM_000875.5	ENSP00000497069.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T;.;T;.;.
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	.;.;D;D;D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.39	T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.4	L;.;L;.;.
PhyloP100		5.0
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	0.34	.;.;N;N;N
REVEL	Benign	0.22
Sift	Benign	0.63	.;.;T;T;T
Sift4G	Benign	0.39	.;.;T;T;T
Polyphen		0.0040	B;D;B;D;.
Vest4		0.55, 0.62
MutPred		0.57		Loss of MoRF binding (P = 0.0047);Loss of MoRF binding (P = 0.0047);Loss of MoRF binding (P = 0.0047);Loss of MoRF binding (P = 0.0047);.;
MVP		0.90
MPC		0.90
ClinPred		0.70	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.57
gMVP		0.91

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: rs33958176; hg19: chr15-99454613;