15-98649655-T-G

Position:

• chr15-98649655-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_000875.5(IGF1R):​c.74T>G​(p.Leu25Arg) 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. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: IGF1R NM_000875.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.09

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]

IRAIN (HGNC:50365): (IGF1R antisense imprinted non-protein coding RNA) This gene expresses a long non-coding RNA in antisense to the insulin-like growth factor type I receptor (IGF1R) gene. This transcript is imprinted and expressed from the paternal allele. It interacts with chromatin and may promote long-range DNA interactions that influence the regulation of gene expression. [provided by RefSeq, Nov 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 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). The gene has 12 curated pathogenic missense variants (we use a threshold of 10). The gene has 19 curated benign missense variants. GenCC has associacion of the gene with growth delay due to insulin-like growth factor I resistance.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2942466).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGF1R	NM_000875.5	c.74T>G	p.Leu25Arg	missense_variant	1/21	ENST00000650285.1	NP_000866.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGF1R	ENST00000650285.1	c.74T>G	p.Leu25Arg	missense_variant	1/21		NM_000875.5	ENSP00000497069.1
IGF1R	ENST00000559925.5	n.74T>G		non_coding_transcript_exon_variant	1/10	1
IGF1R	ENST00000649865.1	c.74T>G	p.Leu25Arg	missense_variant	1/21			ENSP00000496919.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 24, 2024

The c.74T>G (p.L25R) alteration is located in exon 1 (coding exon 1) of the IGF1R gene. This alteration results from a T to G substitution at nucleotide position 74, causing the leucine (L) at amino acid position 25 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 30, 2024

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.55	D;.;D;.
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.037
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.70	.;.;T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.29	T;T;T;T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	0.90	L;.;L;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.9	.;.;N;N
REVEL	Uncertain	0.53
Sift	Uncertain	0.025	.;.;D;D
Sift4G	Benign	0.068	.;.;T;T
Polyphen		0.023	B;B;B;B
Vest4		0.79, 0.72
MutPred		0.41		Gain of solvent accessibility (P = 0.0314);Gain of solvent accessibility (P = 0.0314);Gain of solvent accessibility (P = 0.0314);Gain of solvent accessibility (P = 0.0314);
MVP		0.98
MPC		1.0
ClinPred		0.69	D
GERP RS		3.8
Varity_R		0.48
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr15-99192884;