15-98707869-G-C

Position:

• chr15-98707869-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_000875.5(IGF1R):​c.402G>C​(p.Arg134Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 1.04

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), IGF1R. . Trascript score misZ 4.6449 (greater than threshold 3.09). GenCC has associacion of gene with growth delay due to insulin-like growth factor I resistance.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGF1R	NM_000875.5	c.402G>C	p.Arg134Ser	missense_variant	2/21	ENST00000650285.1	NP_000866.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGF1R	ENST00000650285.1	c.402G>C	p.Arg134Ser	missense_variant	2/21		NM_000875.5	ENSP00000497069	P4
IGF1R	ENST00000559925.5	n.402G>C		non_coding_transcript_exon_variant	2/10	1
IGF1R	ENST00000649865.1	c.402G>C	p.Arg134Ser	missense_variant	2/21			ENSP00000496919	A1
IGF1R	ENST00000558355.1	c.39G>C	p.Arg13Ser	missense_variant	1/2	2		ENSP00000453630

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.55	D;.;D;.;D
Eigen	Benign	-0.018
Eigen_PC	Benign	0.034
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.71	.;.;T;T;T
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.69	D;D;D;D;D
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	1.9	L;.;L;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.23	.;.;N;N;N
REVEL	Uncertain	0.51
Sift	Benign	0.12	.;.;T;T;T
Sift4G	Benign	0.70	.;.;T;T;T
Polyphen		0.51	P;P;P;P;.
Vest4		0.81, 0.78
MutPred		0.81		Loss of MoRF binding (P = 0.0297);Loss of MoRF binding (P = 0.0297);Loss of MoRF binding (P = 0.0297);Loss of MoRF binding (P = 0.0297);.;
MVP		0.97
MPC		1.5
ClinPred		0.55	D
GERP RS		2.4
Varity_R		0.34
gMVP		0.80

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: rs35385418; hg19: chr15-99251098;