rs1815009

chr15-98961442-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000875.5(IGF1R):c.*4000C>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 0.671 in 233,136 control chromosomes in the GnomAD database, including 53,938 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (33620 hom., cov: 33)
  • Exomes 𝑓: 0.70 (20318 hom.)
• Consequence: IGF1R NM_000875.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0300

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 15-98961442-C-T is Benign according to our data. Variant chr15-98961442-C-T is described in ClinVar as [Benign]. Clinvar id is 317570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.747 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IGF1R	NM_000875.5	c.*4000C>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.*4000C>T		3_prime_UTR_variant	21/21		NM_000875.5	P4
SYNM-AS1	ENST00000559468.1	n.348+4547G>A		intron_variant, non_coding_transcript_variant		4
IGF1R	ENST00000649865.1	c.*4000C>T		3_prime_UTR_variant	21/21			A1

Frequencies

GnomAD3 genomes AF: 0.653 AC: 99292 AN: 151946 Hom.: 33608 Cov.: 33

Gnomad AFR AF: 0.473

Gnomad AMI AF: 0.578

Gnomad AMR AF: 0.629

Gnomad ASJ AF: 0.709

Gnomad EAS AF: 0.533

Gnomad SAS AF: 0.680

Gnomad FIN AF: 0.789

Gnomad MID AF: 0.620

Gnomad NFE AF: 0.753

Gnomad OTH AF: 0.666

GnomAD4 exome AF: 0.703 AC: 56997 AN: 81072 Hom.: 20318 Cov.: 0 AF XY: 0.705 AC XY: 26301 AN XY: 37282

Gnomad4 AFR exome AF: 0.473

Gnomad4 AMR exome AF: 0.633

Gnomad4 ASJ exome AF: 0.703

Gnomad4 EAS exome AF: 0.596

Gnomad4 SAS exome AF: 0.714

Gnomad4 FIN exome AF: 0.804

Gnomad4 NFE exome AF: 0.749

Gnomad4 OTH exome AF: 0.695

GnomAD4 genome AF: 0.653 AC: 99340 AN: 152064 Hom.: 33620 Cov.: 33 AF XY: 0.652 AC XY: 48436 AN XY: 74332

Gnomad4 AFR AF: 0.473

Gnomad4 AMR AF: 0.629

Gnomad4 ASJ AF: 0.709

Gnomad4 EAS AF: 0.533

Gnomad4 SAS AF: 0.681

Gnomad4 FIN AF: 0.789

Gnomad4 NFE AF: 0.753

Gnomad4 OTH AF: 0.668

Alfa AF: 0.725 Hom.: 39808

Bravo AF: 0.633

Asia WGS AF: 0.620 AC: 2155 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 16, 2019

This variant is associated with the following publications: (PMID: 30365147) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
Cadd	Benign	5.3
Dann	Benign	0.74

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: rs1815009; hg19: chr15-99504671; COSMIC: COSV51411694; COSMIC: COSV51411694;