chr15-98896768-T-C

Variant names:

• chr15-98896768-T-C
• rs45597432
• NM_000875.5:c.965T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000875.5(IGF1R):​c.965T>C​(p.Ile322Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IGF1R NM_000875.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.86
• Publications: 5 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.123354584).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGF1R	NM_000875.5	c.965T>C	p.Ile322Thr	missense_variant	Exon 4 of 21	ENST00000650285.1	NP_000866.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGF1R	ENST00000650285.1	c.965T>C	p.Ile322Thr	missense_variant	Exon 4 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	Benign	0.11
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	20
DANN	Benign	0.86
DEOGEN2	Uncertain	0.49	T;.;T;.;.
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.10
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.81	.;.;T;T;T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.12	T;T;T;T;T
MetaSVM	Uncertain	0.18	D
MutationAssessor	Benign	-0.79	N;.;N;.;.
PhyloP100		1.9
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	1.6	.;.;N;N;N
REVEL	Benign	0.27
Sift	Benign	0.55	.;.;T;T;T
Sift4G	Benign	0.72	.;.;T;T;T
Polyphen		0.0	B;B;B;B;.
Vest4		0.16, 0.20
MutPred		0.44		Gain of phosphorylation at I322 (P = 0.0218);Gain of phosphorylation at I322 (P = 0.0218);Gain of phosphorylation at I322 (P = 0.0218);Gain of phosphorylation at I322 (P = 0.0218);.;
MVP		0.64
MPC		0.78
ClinPred		0.40	T
GERP RS		4.7
Varity_R		0.17
gMVP		0.45

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: rs45597432; hg19: chr15-99439997;