15-98957115-C-G

Variant names:

• chr15-98957115-C-G
• rs371462352
• NM_000875.5:c.3777C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_000875.5(IGF1R):​c.3777C>G​(p.Phe1259Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. F1259F) 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: 5.01
• 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]

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000875.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGF1R	NM_000875.5	MANE Select	c.3777C>G	p.Phe1259Leu	missense	Exon 21 of 21	NP_000866.1	P08069
	IGF1R	NM_001291858.2		c.3774C>G	p.Phe1258Leu	missense	Exon 21 of 21	NP_001278787.1	C9J5X1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGF1R	ENST00000650285.1	MANE Select	c.3777C>G	p.Phe1259Leu	missense	Exon 21 of 21	ENSP00000497069.1	P08069
	IGF1R	ENST00000649865.1		c.3774C>G	p.Phe1258Leu	missense	Exon 21 of 21	ENSP00000496919.1	C9J5X1
	IGF1R	ENST00000558751.1	TSL:4	n.371C>G		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		5.0
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.6	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.86		Loss of methylation at K1254 (P = 0.1096)
MVP		0.96
MPC		0.38
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.93
gMVP		0.81

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: rs371462352; hg19: chr15-99500344;