15-98707828-G-C

Variant names:

• chr15-98707828-G-C
• rs1555434208
• NM_000875.5:c.361G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_000875.5(IGF1R):​c.361G>C​(p.Glu121Gln) 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. 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. E121K) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IGF1R NM_000875.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.86
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-98707828-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 446754.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.909

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGF1R	NM_000875.5	MANE Select	c.361G>C	p.Glu121Gln	missense	Exon 2 of 21	NP_000866.1
	IGF1R	NM_001291858.2		c.361G>C	p.Glu121Gln	missense	Exon 2 of 21	NP_001278787.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGF1R	ENST00000650285.1	MANE Select	c.361G>C	p.Glu121Gln	missense	Exon 2 of 21	ENSP00000497069.1
	IGF1R	ENST00000559925.5	TSL:1	n.361G>C		non_coding_transcript_exon	Exon 2 of 10
	IGF1R	ENST00000649865.1		c.361G>C	p.Glu121Gln	missense	Exon 2 of 21	ENSP00000496919.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		9.9
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-2.5	N
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.050	T
Polyphen		1.0	D
Vest4		0.89
MutPred		0.74		Loss of sheet (P = 0.0315)
MVP		0.93
MPC		1.6
ClinPred		1.0	D
GERP RS		5.4
PromoterAI		-0.021	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.79
gMVP		0.79

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

Other links and lift over

dbSNP: rs1555434208; hg19: chr15-99251057;