rs1555434208

Positions:

• chr15-98707828-G-A
• chr15-98707828-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Moderate PP5_Moderate

The NM_000875.5(IGF1R):​c.361G>A​(p.Glu121Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: IGF1R NM_000875.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 B:1
• Conservation: PhyloP100: 9.86

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 Likely_pathogenic. Variant got 7 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.937
• PP5: Variant 15-98707828-G-A is Pathogenic according to our data. Variant chr15-98707828-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 446754.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGF1R	NM_000875.5	c.361G>A	p.Glu121Lys	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.361G>A	p.Glu121Lys	missense_variant	2/21		NM_000875.5	ENSP00000497069	P4
IGF1R	ENST00000559925.5	n.361G>A		non_coding_transcript_exon_variant	2/10	1
IGF1R	ENST00000649865.1	c.361G>A	p.Glu121Lys	missense_variant	2/21			ENSP00000496919	A1
IGF1R	ENST00000558355.1			upstream_gene_variant		2		ENSP00000453630

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461884 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Growth delay due to insulin-like growth factor I resistance Pathogenic:1 Benign:1

protective, no assertion criteria provided	literature only	OMIM	Dec 12, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	The variant is not observed in the gnomAD v2.1.1 dataset. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 22130793). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.86). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with IGF1R related disorder . Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.83	D;.;D;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	1.0	.;.;D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.94	D;D;D;D
MetaSVM	Uncertain	0.40	D
MutationAssessor	Benign	1.6	L;.;L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.3	.;.;D;D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	.;.;D;D
Sift4G	Uncertain	0.0040	.;.;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.97, 0.93
MutPred		0.80		Gain of MoRF binding (P = 0.0165);Gain of MoRF binding (P = 0.0165);Gain of MoRF binding (P = 0.0165);Gain of MoRF binding (P = 0.0165);
MVP		0.97
MPC		1.7
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.91
gMVP		0.90

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: rs1555434208; hg19: chr15-99251057; COSMIC: COSV51293345; COSMIC: COSV51293345;