NM_000875.5:c.119G>A

Variant names:

• chr15-98707586-G-A
• rs1409058783
• NM_000875.5:c.119G>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_000875.5(IGF1R):​c.119G>A​(p.Arg40His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: IGF1R NM_000875.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U: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 Uncertain_significance. Variant got 4 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.816

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGF1R	NM_000875.5	c.119G>A	p.Arg40His	missense_variant	Exon 2 of 21	ENST00000650285.1	NP_000866.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGF1R	ENST00000650285.1	c.119G>A	p.Arg40His	missense_variant	Exon 2 of 21		NM_000875.5	ENSP00000497069.1
IGF1R	ENST00000559925.5	n.119G>A		non_coding_transcript_exon_variant	Exon 2 of 10	1
IGF1R	ENST00000649865.1	c.119G>A	p.Arg40His	missense_variant	Exon 2 of 21			ENSP00000496919.1
IGF1R	ENST00000558355.1	c.-245G>A		upstream_gene_variant		2		ENSP00000453630.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

May 12, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	D;.;D;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	.;.;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.82	D;D;D;D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Pathogenic	3.4	M;.;M;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.9	.;.;D;D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0010	.;.;D;D
Sift4G	Uncertain	0.0030	.;.;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.54, 0.52
MutPred		0.67		Loss of catalytic residue at R40 (P = 0.0318);Loss of catalytic residue at R40 (P = 0.0318);Loss of catalytic residue at R40 (P = 0.0318);Loss of catalytic residue at R40 (P = 0.0318);
MVP		0.90
MPC		1.7
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.67
gMVP		0.85

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: rs1409058783; hg19: chr15-99250815; COSMIC: COSV51407980; COSMIC: COSV51407980;