rs45615734

Positions:

• chr15-98916700-C-G
• chr15-98916700-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The NM_000875.5(IGF1R):​c.2025C>G​(p.Asp675Glu) 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 benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IGF1R NM_000875.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.91

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 Likely_benign. Variant got -1 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.05440682).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGF1R	NM_000875.5	c.2025C>G	p.Asp675Glu	missense_variant	10/21	ENST00000650285.1	NP_000866.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGF1R	ENST00000650285.1	c.2025C>G	p.Asp675Glu	missense_variant	10/21		NM_000875.5	ENSP00000497069	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	0.0040
DANN	Benign	0.93
DEOGEN2	Benign	0.40	T;.;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.62	.;.;T;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.054	T;T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.6	L;.;L;.
MutationTaster	Benign	0.65	N;N
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-0.21	.;.;N;N
REVEL	Benign	0.083
Sift	Benign	0.94	.;.;T;T
Sift4G	Benign	1.0	.;.;T;T
Polyphen		0.015	B;P;B;P
Vest4		0.088, 0.087
MutPred		0.47		Gain of methylation at K672 (P = 0.0694);Gain of methylation at K672 (P = 0.0694);Gain of methylation at K672 (P = 0.0694);Gain of methylation at K672 (P = 0.0694);
MVP		0.63
MPC		0.60
ClinPred		0.20	T
GERP RS		-2.8
Varity_R		0.052
gMVP		0.28

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-99459929;