rs34061581

chr15-98922369-A-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 same amino acid change has been previously reported as Likely benignin UniProt. Synonymous variant affecting the same amino acid position (i.e. H808H) has been classified as Likely benign.

• 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 where missense usually causes diseases, IGF1R
• BP4: Computational evidence support a benign effect (MetaRNN=0.26765102).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IGF1R	NM_000875.5	c.2423A>G	p.His808Arg	missense_variant	11/21	ENST00000650285.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGF1R	ENST00000650285.1	c.2423A>G	p.His808Arg	missense_variant	11/21		NM_000875.5	P4
IGF1R	ENST00000649865.1	c.2423A>G	p.His808Arg	missense_variant	11/21			A1
IGF1R	ENST00000561049.1	n.614A>G		non_coding_transcript_exon_variant	2/3	5

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
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;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.79	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;