15-98958352-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000875.5(IGF1R):c.*910C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.183 in 220,666 control chromosomes in the GnomAD database, including 4,178 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.19 (3007 hom., cov: 29)
  • Exomes 𝑓: 0.16 (1171 hom.)
• Consequence: IGF1R NM_000875.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.286

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 15-98958352-C-T is Benign according to our data. Variant chr15-98958352-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 317492.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.227 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IGF1R	NM_000875.5	c.*910C>T		3_prime_UTR_variant	21/21	ENST00000650285.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGF1R	ENST00000650285.1	c.*910C>T		3_prime_UTR_variant	21/21		NM_000875.5	P4
SYNM-AS1	ENST00000559468.1	n.349-3964G>A		intron_variant, non_coding_transcript_variant		4
IGF1R	ENST00000649865.1	c.*910C>T		3_prime_UTR_variant	21/21			A1

Frequencies

GnomAD3 genomes AF: 0.193 AC: 29129 AN: 151014 Hom.: 3005 Cov.: 29

Gnomad AFR AF: 0.157

Gnomad AMI AF: 0.284

Gnomad AMR AF: 0.183

Gnomad ASJ AF: 0.166

Gnomad EAS AF: 0.0240

Gnomad SAS AF: 0.0706

Gnomad FIN AF: 0.249

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.230

Gnomad OTH AF: 0.191

GnomAD4 exome AF: 0.160 AC: 11133 AN: 69544 Hom.: 1171 Cov.: 0 AF XY: 0.159 AC XY: 5094 AN XY: 32068

Gnomad4 AFR exome AF: 0.138

Gnomad4 AMR exome AF: 0.160

Gnomad4 ASJ exome AF: 0.144

Gnomad4 EAS exome AF: 0.0233

Gnomad4 SAS exome AF: 0.0641

Gnomad4 FIN exome AF: 0.250

Gnomad4 NFE exome AF: 0.198

Gnomad4 OTH exome AF: 0.165

GnomAD4 genome AF: 0.193 AC: 29148 AN: 151122 Hom.: 3007 Cov.: 29 AF XY: 0.189 AC XY: 13945 AN XY: 73766

Gnomad4 AFR AF: 0.157

Gnomad4 AMR AF: 0.183

Gnomad4 ASJ AF: 0.166

Gnomad4 EAS AF: 0.0240

Gnomad4 SAS AF: 0.0709

Gnomad4 FIN AF: 0.249

Gnomad4 NFE AF: 0.230

Gnomad4 OTH AF: 0.189

Alfa AF: 0.214 Hom.: 7267

Bravo AF: 0.190

Asia WGS AF: 0.0830 AC: 290 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	2.9
Dann	Benign	0.59

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

LitVar

Other links and lift over

dbSNP: rs702497; hg19: chr15-99501581; COSMIC: COSV51274122; COSMIC: COSV51274122;