rs121912426

Variant names:

• chr15-98707880-G-A
• rs121912426
• NM_000875.5:c.413G>A

Your query was ambiguous. Multiple possible variants found:

• chr15-98707880-G-A
• chr15-98707880-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000875.5(IGF1R):​c.413G>A​(p.Arg138Gln) 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 protective (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R138W) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IGF1R NM_000875.5 missense
• Clinical Significance: protective no assertion criteria provided B:1
• Conservation: PhyloP100: 9.86
• Publications: 9 publications found

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]

IGF1R Gene-Disease associations (from GenCC):

• growth delay due to insulin-like growth factor I resistance

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000875.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGF1R	NM_000875.5	MANE Select	c.413G>A	p.Arg138Gln	missense	Exon 2 of 21	NP_000866.1	P08069
	IGF1R	NM_001291858.2		c.413G>A	p.Arg138Gln	missense	Exon 2 of 21	NP_001278787.1	C9J5X1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGF1R	ENST00000650285.1	MANE Select	c.413G>A	p.Arg138Gln	missense	Exon 2 of 21	ENSP00000497069.1	P08069
	IGF1R	ENST00000559925.5	TSL:1	n.413G>A		non_coding_transcript_exon	Exon 2 of 10
	IGF1R	ENST00000649865.1		c.413G>A	p.Arg138Gln	missense	Exon 2 of 21	ENSP00000496919.1	C9J5X1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: protective

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	-	Growth delay due to insulin-like growth factor I resistance (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.85	D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		9.9
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.2	D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.91		Loss of MoRF binding (P = 0.027)
MVP		0.94
MPC		1.7
ClinPred		0.98	D
GERP RS		4.4
PromoterAI		-0.0066	Neutral
Varity_R		0.71
gMVP		0.76
Mutation Taster		=3/97	disease causing

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

Other links and lift over

dbSNP: rs121912426; hg19: chr15-99251109;