NM_000875.5:c.3743G>A

Variant names:

• chr15-98957081-G-A
• NM_000875.5:c.3743G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Strong

The NM_000875.5(IGF1R):​c.3743G>A​(p.Cys1248Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: IGF1R NM_000875.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.97

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]

SYNM-AS1 (HGNC:55421): (SYNM antisense RNA 1)

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the IGF1R gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 12 curated pathogenic missense variants (we use a threshold of 10). The gene has 19 curated benign missense variants. Trascript score misZ: 4.6449 (above the threshold of 3.09). GenCC associations: The gene is linked to growth delay due to insulin-like growth factor I resistance.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.959

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGF1R	NM_000875.5	c.3743G>A	p.Cys1248Tyr	missense_variant	Exon 21 of 21	ENST00000650285.1	NP_000866.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGF1R	ENST00000650285.1	c.3743G>A	p.Cys1248Tyr	missense_variant	Exon 21 of 21		NM_000875.5	ENSP00000497069.1
IGF1R	ENST00000649865.1	c.3740G>A	p.Cys1247Tyr	missense_variant	Exon 21 of 21			ENSP00000496919.1
IGF1R	ENST00000558751.1	n.337G>A		non_coding_transcript_exon_variant	Exon 2 of 2	4
SYNM-AS1	ENST00000559468.1	n.349-2693C>T		intron_variant	Intron 3 of 3	4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jul 17, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in the heterozygous state in two siblings with pre- and postnatal growth delay who inherited the variant from their father with short stature and type 2 diabetes mellitus (PMID: 25153223); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25153223) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;.;D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	.;.;D;D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.7	H;.;H;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-9.6	.;.;D;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0010	.;.;D;D
Sift4G	Pathogenic	0.0010	.;.;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.95, 0.96
MutPred		0.77		Loss of catalytic residue at W1249 (P = 0.0042);.;Loss of catalytic residue at W1249 (P = 0.0042);.;
MVP		0.94
MPC		0.45
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.97
gMVP		0.98

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: chr15-99500310;