15-98649595-C-G

Variant names:

• chr15-98649595-C-G
• NM_000875.5:c.14C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_000875.5(IGF1R):​c.14C>G​(p.Ser5Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,446,910 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: IGF1R NM_000875.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.62

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]

IRAIN (HGNC:50365): (IGF1R antisense imprinted non-protein coding RNA) This gene expresses a long non-coding RNA in antisense to the insulin-like growth factor type I receptor (IGF1R) gene. This transcript is imprinted and expressed from the paternal allele. It interacts with chromatin and may promote long-range DNA interactions that influence the regulation of gene expression. [provided by RefSeq, Nov 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 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=0.18440351).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGF1R	NM_000875.5	c.14C>G	p.Ser5Cys	missense_variant	Exon 1 of 21	ENST00000650285.1	NP_000866.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGF1R	ENST00000650285.1	c.14C>G	p.Ser5Cys	missense_variant	Exon 1 of 21		NM_000875.5	ENSP00000497069.1
IGF1R	ENST00000559925.5	n.14C>G		non_coding_transcript_exon_variant	Exon 1 of 10	1
IGF1R	ENST00000649865.1	c.14C>G	p.Ser5Cys	missense_variant	Exon 1 of 21			ENSP00000496919.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1446910 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 720464

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: 9.08e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jul 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 5 of the IGF1R protein (p.Ser5Cys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with IGF1R-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	0.00048	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.41	T;.;T;.
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.069
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.61	.;.;T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.18	T;T;T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	0.34	N;.;N;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.53	.;.;N;N
REVEL	Benign	0.27
Sift	Uncertain	0.013	.;.;D;D
Sift4G	Uncertain	0.031	.;.;D;D
Polyphen		0.21	B;B;B;B
Vest4		0.23, 0.26
MutPred		0.24		Loss of glycosylation at S5 (P = 0.0013);Loss of glycosylation at S5 (P = 0.0013);Loss of glycosylation at S5 (P = 0.0013);Loss of glycosylation at S5 (P = 0.0013);
MVP		0.71
MPC		0.71
ClinPred		0.38	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.17
gMVP		0.64

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-99192824;