chr15-98649583-T-A

Position:

• chr15-98649583-T-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000875.5(IGF1R):​c.2T>A​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: IGF1R NM_000875.5 start_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.19

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:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-98649583-T-A is Pathogenic according to our data. Variant chr15-98649583-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2664702.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IGF1R	NM_000875.5	c.2T>A	p.Met1?	start_lost	1/21	ENST00000650285.1
IRAIN	NR_126453.2	n.1205A>T		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGF1R	ENST00000650285.1	c.2T>A	p.Met1?	start_lost	1/21		NM_000875.5	P4
IGF1R	ENST00000559925.5	n.2T>A		non_coding_transcript_exon_variant	1/10	1
IGF1R	ENST00000649865.1	c.2T>A	p.Met1?	start_lost	1/21			A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Growth delay due to insulin-like growth factor I resistance Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genetics and Molecular Pathology, SA Pathology

Jun 09, 2023

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	24
DANN	Benign	0.95
DEOGEN2	Benign	0.42	T;.;T;.
Eigen	Benign	0.15
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.64	D
LIST_S2	Uncertain	0.90	.;.;D;D
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Benign	-0.57	T
MutationTaster	Benign	1.0	D;D
PROVEAN	Benign	-0.30	.;.;N;N
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	.;.;D;D
Sift4G	Pathogenic	0.0	.;.;D;D
Polyphen		0.85	P;P;P;P
Vest4		0.86, 0.78
MutPred		0.99		Loss of stability (P = 0.0012);Loss of stability (P = 0.0012);Loss of stability (P = 0.0012);Loss of stability (P = 0.0012);
MVP		0.90
ClinPred		0.99	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.80
gMVP		0.91

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: chr15-99192812;