15-98934996-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1 PM2 PP2 BP4

The NM_000875.5(IGF1R):c.3129G>T(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. Synonymous variant affecting the same amino acid position (i.e. E1043E) has been classified as Benign.

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

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 4 ACMG points.

• PM1: In a domain Protein kinase (size 275) in uniprot entity IGF1R_HUMAN there are 10 pathogenic changes around while only 1 benign (91%) in NM_000875.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, IGF1R
• BP4: Computational evidence support a benign effect (MetaRNN=0.3254441).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IGF1R	NM_000875.5	c.3129G>T	p.Glu1043Asp	missense_variant	16/21	ENST00000650285.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGF1R	ENST00000650285.1	c.3129G>T	p.Glu1043Asp	missense_variant	16/21		NM_000875.5	P4
IGF1R	ENST00000560972.1	n.260-320G>T		intron_variant, non_coding_transcript_variant		1
IGF1R	ENST00000649865.1	c.3126G>T	p.Glu1042Asp	missense_variant	16/21			A1

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	Benign	0.73	D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.33	T;T;T;T
MetaSVM	Uncertain	0.072	D
MutationAssessor	Benign	0.34	N;.;N;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.88	D
Polyphen		0.11	B;P;B;P
Vest4		0.61, 0.58
MutPred		0.61		Loss of disorder (P = 0.1423);.;Loss of disorder (P = 0.1423);.;
MVP		0.84
MPC		1.3
ClinPred		0.94	D
GERP RS		-9.5
Varity_R		0.59
gMVP		0.88

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

LitVar

Other links and lift over

dbSNP: rs2229765; hg19: chr15-99478225;