rs34061581

Variant names:

• chr15-98922369-A-G
• rs34061581
• NM_000875.5:c.2423A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_000875.5(IGF1R):​c.2423A>G​(p.His808Arg) 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 benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IGF1R NM_000875.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.49

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 2 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=0.26765102).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGF1R	NM_000875.5	c.2423A>G	p.His808Arg	missense_variant	Exon 11 of 21	ENST00000650285.1	NP_000866.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGF1R	ENST00000650285.1	c.2423A>G	p.His808Arg	missense_variant	Exon 11 of 21		NM_000875.5	ENSP00000497069.1
IGF1R	ENST00000649865.1	c.2423A>G	p.His808Arg	missense_variant	Exon 11 of 21			ENSP00000496919.1
IGF1R	ENST00000561049.1	n.614A>G		non_coding_transcript_exon_variant	Exon 2 of 3	5
IGF1R	ENST00000560144.1	n.*381A>G		downstream_gene_variant		3		ENSP00000456950.1

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	Uncertain	0.44
BayesDel_addAF	Benign	-0.00088	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.78	D;.;D;.
Eigen	Benign	0.089
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.81	.;.;T;T
M_CAP	Benign	0.0094	T
MetaRNN	Benign	0.27	T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.8	L;.;L;.
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-3.2	.;.;D;D
REVEL	Benign	0.13
Sift	Benign	0.10	.;.;T;T
Sift4G	Benign	0.16	.;.;T;T
Polyphen		0.013	B;B;B;B
Vest4		0.26, 0.27
MutPred		0.40		Loss of catalytic residue at H808 (P = 0.012);Loss of catalytic residue at H808 (P = 0.012);Loss of catalytic residue at H808 (P = 0.012);Loss of catalytic residue at H808 (P = 0.012);
MVP		0.68
MPC		0.76
ClinPred		0.87	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.41
gMVP		0.50

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: rs34061581; hg19: chr15-99465598;