15-98934996-G-C

Variant names:

• chr15-98934996-G-C
• rs2229765
• NM_000875.5:c.3129G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_000875.5(IGF1R):​c.3129G>C​(p.Glu1043Asp) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1043Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: IGF1R NM_000875.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.148
• Publications: 0 publications found

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]

IGF1R Gene-Disease associations (from GenCC):

• growth delay due to insulin-like growth factor I resistance

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a domain Protein kinase (size 275) in uniprot entity IGF1R_HUMAN there are 13 pathogenic changes around while only 0 benign (100%) in NM_000875.5
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34019148).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGF1R	NM_000875.5	c.3129G>C	p.Glu1043Asp	missense_variant	Exon 16 of 21	ENST00000650285.1	NP_000866.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGF1R	ENST00000650285.1	c.3129G>C	p.Glu1043Asp	missense_variant	Exon 16 of 21		NM_000875.5	ENSP00000497069.1
IGF1R	ENST00000560972.1	n.260-320G>C		intron_variant	Intron 3 of 3	1
IGF1R	ENST00000649865.1	c.3126G>C	p.Glu1042Asp	missense_variant	Exon 16 of 21			ENSP00000496919.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 46

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Uncertain	0.088	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.86	D;.;D;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.0	.;.;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.34	T;T;T;T
MetaSVM	Uncertain	0.072	D
MutationAssessor	Benign	0.34	N;.;N;.
PhyloP100		-0.15
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	0.0	.;.;N;N
REVEL	Benign	0.0
Sift	Pathogenic	0.0	.;.;D;D
Sift4G	Pathogenic	0.0	.;.;T;T
Vest4		0.0
ClinPred		0.94	D
GERP RS		-9.5
Varity_R		0.59
gMVP		0.88
Mutation Taster		=54/46	polymorphism

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

Other links and lift over

dbSNP: rs2229765; hg19: chr15-99478225;