rs45597432

Positions:

• chr15-98896768-T-A
• chr15-98896768-T-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.965T>A​(p.Ile322Asn) 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. 13/21 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: 1.86

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 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=0.23915368).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IGF1R	NM_000875.5	c.965T>A	p.Ile322Asn	missense_variant	4/21	ENST00000650285.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGF1R	ENST00000650285.1	c.965T>A	p.Ile322Asn	missense_variant	4/21		NM_000875.5	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	0.13
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Uncertain	0.51	D;.;D;.;.
Eigen	Benign	-0.16
Eigen_PC	Benign	0.046
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.85	.;.;T;T;T
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.24	T;T;T;T;T
MetaSVM	Uncertain	0.66	D
MutationAssessor	Benign	1.3	L;.;L;.;.
MutationTaster	Benign	0.78	D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	0.66	.;.;N;N;N
REVEL	Benign	0.27
Sift	Benign	0.21	.;.;T;T;T
Sift4G	Benign	0.51	.;.;T;T;T
Polyphen		0.0	B;B;B;B;.
Vest4		0.34, 0.31
MutPred		0.47		Gain of disorder (P = 0.0573);Gain of disorder (P = 0.0573);Gain of disorder (P = 0.0573);Gain of disorder (P = 0.0573);.;
MVP		0.79
MPC		1.1
ClinPred		0.50	T
GERP RS		4.7
Varity_R		0.39
gMVP		0.63

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: chr15-99439997;