rs121912427

Positions:

• chr15-98707902-A-C
• chr15-98707902-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_000875.5(IGF1R):​c.435A>C​(p.Lys145Asn) variant causes a missense change involving the alteration of a non-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).

• Frequency: Genomes: not found (cov: 32)
• Consequence: IGF1R NM_000875.5 missense
• Clinical Significance: protective no assertion criteria provided B:1
• Conservation: PhyloP100: 0.0700

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), IGF1R. . Trascript score misZ 4.6449 (greater than threshold 3.09). GenCC has associacion of gene with growth delay due to insulin-like growth factor I resistance.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.859

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGF1R	NM_000875.5	c.435A>C	p.Lys145Asn	missense_variant	2/21	ENST00000650285.1	NP_000866.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGF1R	ENST00000650285.1	c.435A>C	p.Lys145Asn	missense_variant	2/21		NM_000875.5	ENSP00000497069.1
IGF1R	ENST00000559925.5	n.435A>C		non_coding_transcript_exon_variant	2/10	1
IGF1R	ENST00000649865.1	c.435A>C	p.Lys145Asn	missense_variant	2/21			ENSP00000496919.1
IGF1R	ENST00000558355.1	c.72A>C	p.Lys24Asn	missense_variant	1/2	2		ENSP00000453630.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: protective

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

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

protective, no assertion criteria provided

literature only

OMIM

Dec 04, 2003

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Uncertain	0.021	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D;.;D;.;D
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.74	D
LIST_S2	Pathogenic	0.98	.;.;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D
MetaSVM	Uncertain	-0.078	T
MutationAssessor	Uncertain	2.2	M;.;M;.;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-4.0	.;.;D;D;D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0010	.;.;D;D;D
Sift4G	Uncertain	0.0030	.;.;D;D;D
Polyphen		1.0	D;D;D;D;.
Vest4		0.92, 0.85
MutPred		0.86		Loss of ubiquitination at K145 (P = 0.0224);Loss of ubiquitination at K145 (P = 0.0224);Loss of ubiquitination at K145 (P = 0.0224);Loss of ubiquitination at K145 (P = 0.0224);.;
MVP		0.89
MPC		1.7
ClinPred		1.0	D
GERP RS		-6.2
Varity_R		0.88
gMVP		0.88

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: rs121912427; hg19: chr15-99251131;