NM_000875.5:c.1162G>C

Variant names:

• chr15-98899536-G-C
• rs45445894
• NM_000875.5:c.1162G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000875.5(IGF1R):​c.1162G>C​(p.Val388Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. V388M) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: IGF1R NM_000875.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.88
• Publications: 19 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGF1R	NM_000875.5	c.1162G>C	p.Val388Leu	missense_variant	Exon 5 of 21	ENST00000650285.1	NP_000866.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGF1R	ENST00000650285.1	c.1162G>C	p.Val388Leu	missense_variant	Exon 5 of 21		NM_000875.5	ENSP00000497069.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Benign	21
DANN	Benign	0.92
DEOGEN2	Uncertain	0.47	T;.;T;.;.
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.027
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.91	.;.;D;D;D
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.51	D;D;D;D;D
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.80	N;.;N;.;.
PhyloP100		5.9
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	0.99	.;.;N;N;N
REVEL	Uncertain	0.43
Sift	Benign	1.0	.;.;T;T;T
Sift4G	Benign	1.0	.;.;T;T;T
Polyphen		0.0010	B;B;B;B;.
Vest4		0.39, 0.41
MutPred		0.56		Loss of methylation at R391 (P = 0.122);Loss of methylation at R391 (P = 0.122);Loss of methylation at R391 (P = 0.122);Loss of methylation at R391 (P = 0.122);.;
MVP		0.95
MPC		0.65
ClinPred		0.85	D
GERP RS		4.5
Varity_R		0.21
gMVP		0.74
Mutation Taster		=57/43	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: rs45445894; hg19: chr15-99442765;