NM_000875.5:c.2482G>C

Variant names:

• chr15-98922428-G-C
• rs35224135
• NM_000875.5:c.2482G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_000875.5(IGF1R):​c.2482G>C​(p.Ala828Pro) 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 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. A828T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: IGF1R NM_000875.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.92

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the IGF1R gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 12 curated pathogenic missense variants (we use a threshold of 10). The gene has 19 curated benign missense variants. Trascript score misZ: 4.6449 (above the threshold of 3.09). GenCC associations: The gene is linked to growth delay due to insulin-like growth factor I resistance.
• BP4: Computational evidence support a benign effect (MetaRNN=0.33961344).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGF1R	NM_000875.5	c.2482G>C	p.Ala828Pro	missense_variant	Exon 11 of 21	ENST00000650285.1	NP_000866.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGF1R	ENST00000650285.1	c.2482G>C	p.Ala828Pro	missense_variant	Exon 11 of 21		NM_000875.5	ENSP00000497069.1
IGF1R	ENST00000649865.1	c.2482G>C	p.Ala828Pro	missense_variant	Exon 11 of 21			ENSP00000496919.1
IGF1R	ENST00000561049.1	n.673G>C		non_coding_transcript_exon_variant	Exon 2 of 3	5
IGF1R	ENST00000560144.1	n.*440G>C		downstream_gene_variant		3		ENSP00000456950.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D;.;D;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.95	.;.;D;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.34	T;T;T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Uncertain	2.6	M;.;M;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.94	.;.;N;N
REVEL	Benign	0.14
Sift	Benign	0.17	.;.;T;T
Sift4G	Benign	0.25	.;.;T;T
Polyphen		0.50	P;D;P;D
Vest4		0.51, 0.59
MutPred		0.38		Gain of catalytic residue at P827 (P = 0.0126);Gain of catalytic residue at P827 (P = 0.0126);Gain of catalytic residue at P827 (P = 0.0126);Gain of catalytic residue at P827 (P = 0.0126);
MVP		0.68
MPC		1.8
ClinPred		0.86	D
GERP RS		5.4
Varity_R		0.35
gMVP		0.82

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: rs35224135; hg19: chr15-99465657;