15-98930243-G-T

Variant names:

• chr15-98930243-G-T
• rs45493995
• NM_000875.5:c.2894G>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_000875.5(IGF1R):​c.2894G>T​(p.Ser965Ile) 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: 33)
• Consequence: IGF1R NM_000875.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.79

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the IGF1R gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 12 curated pathogenic missense variants (we use a threshold of 10). The gene has 19 curated benign missense variants. Trascript score misZ: 4.6449 (above the threshold of 3.09). GenCC associations: The gene is linked to growth delay due to insulin-like growth factor I resistance.
• BP4: Computational evidence support a benign effect (MetaRNN=0.118920684).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGF1R	NM_000875.5	c.2894G>T	p.Ser965Ile	missense_variant	Exon 15 of 21	ENST00000650285.1	NP_000866.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGF1R	ENST00000650285.1	c.2894G>T	p.Ser965Ile	missense_variant	Exon 15 of 21		NM_000875.5	ENSP00000497069.1
IGF1R	ENST00000560972.1	n.197G>T		non_coding_transcript_exon_variant	Exon 3 of 4	1
IGF1R	ENST00000649865.1	c.2891G>T	p.Ser964Ile	missense_variant	Exon 15 of 21			ENSP00000496919.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Uncertain	0.63	D;.;D;.
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.28
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	.;.;D;D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.12	T;T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	-0.34	N;.;N;.
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.5	.;.;N;D
REVEL	Benign	0.099
Sift	Benign	0.14	.;.;T;T
Sift4G	Benign	0.26	.;.;T;T
Polyphen		0.0010	B;B;B;B
Vest4		0.15, 0.17
MutPred		0.35		Loss of disorder (P = 5e-04);.;Loss of disorder (P = 5e-04);.;
MVP		0.67
MPC		0.73
ClinPred		0.34	T
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.060
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs45493995; hg19: chr15-99473472;