15-98916776-G-C

Variant names:

• chr15-98916776-G-C
• rs201631492
• NM_000875.5:c.2101G>C

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.2101G>C​(p.Ala701Pro) 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. 14/21 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: 3.38

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=0.15128374).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGF1R	NM_000875.5	c.2101G>C	p.Ala701Pro	missense_variant	Exon 10 of 21	ENST00000650285.1	NP_000866.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGF1R	ENST00000650285.1	c.2101G>C	p.Ala701Pro	missense_variant	Exon 10 of 21		NM_000875.5	ENSP00000497069.1

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	0.087
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	22
DANN	Benign	0.90
DEOGEN2	Benign	0.36	T;.;T;.
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.90	.;.;D;D
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.15	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;.;L;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	0.99	.;.;N;N
REVEL	Benign	0.058
Sift	Benign	0.65	.;.;T;T
Sift4G	Benign	0.43	.;.;T;T
Polyphen		0.0020	B;B;B;B
Vest4		0.25, 0.25
MutPred		0.21		Gain of catalytic residue at A701 (P = 0.0343);Gain of catalytic residue at A701 (P = 0.0343);Gain of catalytic residue at A701 (P = 0.0343);Gain of catalytic residue at A701 (P = 0.0343);
MVP		0.33
MPC		0.81
ClinPred		0.59	D
GERP RS		3.2
Varity_R		0.29
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs201631492; hg19: chr15-99460005;