rs45506098

Positions:

• chr15-98916049-C-A
• chr15-98916049-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_000875.5(IGF1R):​c.1914C>A​(p.Asn638Lys) variant causes a missense change involving the alteration of a non-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. Synonymous variant affecting the same amino acid position (i.e. N638N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: IGF1R NM_000875.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0460

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 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGF1R	NM_000875.5	c.1914C>A	p.Asn638Lys	missense_variant	9/21	ENST00000650285.1	NP_000866.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGF1R	ENST00000650285.1	c.1914C>A	p.Asn638Lys	missense_variant	9/21		NM_000875.5	ENSP00000497069	P4
IGF1R	ENST00000559925.5	n.1914C>A		non_coding_transcript_exon_variant	9/10	1
IGF1R	ENST00000649865.1	c.1914C>A	p.Asn638Lys	missense_variant	9/21			ENSP00000496919	A1
IGF1R	ENST00000560144.1	c.145C>A	p.Arg49=	synonymous_variant, NMD_transcript_variant	2/4	3		ENSP00000456950

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.064	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D;.;D;.
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.072
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.92	.;.;D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Uncertain	0.63	D;D;D;D
MetaSVM	Uncertain	0.040	D
MutationAssessor	Pathogenic	3.2	M;.;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-5.3	.;.;D;D
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	.;.;D;D
Sift4G	Uncertain	0.0020	.;.;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.94, 0.93
MutPred		0.57		Gain of methylation at N638 (P = 0.0024);Gain of methylation at N638 (P = 0.0024);Gain of methylation at N638 (P = 0.0024);Gain of methylation at N638 (P = 0.0024);
MVP		0.94
MPC		1.7
ClinPred		0.99	D
GERP RS		1.1
Varity_R		0.83
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: chr15-99459278;