15-98891384-G-C

Variant names:

• chr15-98891384-G-C
• rs1253103806
• NM_000875.5:c.700G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000875.5(IGF1R):​c.700G>C​(p.Glu234Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E234K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IGF1R NM_000875.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.46
• Publications: 8 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, Labcorp Genetics (formerly Invitae), Orphanet

ENSG00000259621 (HGNC:58474):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGF1R	NM_000875.5	c.700G>C	p.Glu234Gln	missense_variant	Exon 3 of 21	ENST00000650285.1	NP_000866.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGF1R	ENST00000650285.1	c.700G>C	p.Glu234Gln	missense_variant	Exon 3 of 21		NM_000875.5	ENSP00000497069.1

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	Benign	0.25
BayesDel_addAF	Uncertain	0.095	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D;.;D;.;T
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.96	.;.;D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.62	D;D;D;D;D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Benign	0.10	N;.;N;.;.
PhyloP100		7.5
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.22	.;.;N;N;N
REVEL	Uncertain	0.51
Sift	Benign	0.49	.;.;T;T;T
Sift4G	Benign	0.64	.;.;T;T;T
Polyphen		0.16	B;P;B;P;.
Vest4		0.33, 0.39
MutPred		0.72		Loss of glycosylation at S238 (P = 0.1214);Loss of glycosylation at S238 (P = 0.1214);Loss of glycosylation at S238 (P = 0.1214);Loss of glycosylation at S238 (P = 0.1214);.;
MVP		0.74
MPC		0.73
ClinPred		0.76	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.76

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: rs1253103806; hg19: chr15-99434613;