rs2654981

Positions:

• chr15-98961900-C-G
• chr15-98961900-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.*4458C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.454 in 233,094 control chromosomes in the GnomAD database, including 24,571 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (15498 hom., cov: 33)
  • Exomes 𝑓: 0.47 (9073 hom.)
• Consequence: IGF1R NM_000875.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.573

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=-0.84).
• BP6: Variant 15-98961900-C-G is Benign according to our data. Variant chr15-98961900-C-G is described in ClinVar as [Benign]. Clinvar id is 317580.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.537 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGF1R	NM_000875.5	c.*4458C>G		3_prime_UTR_variant	21/21	ENST00000650285.1	NP_000866.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGF1R	ENST00000650285.1	c.*4458C>G		3_prime_UTR_variant	21/21		NM_000875.5	ENSP00000497069	P4
SYNM-AS1	ENST00000559468.1	n.348+4089G>C		intron_variant, non_coding_transcript_variant		4
IGF1R	ENST00000649865.1	c.*4458C>G		3_prime_UTR_variant	21/21			ENSP00000496919	A1

Frequencies

GnomAD3 genomes AF: 0.446 AC: 67804 AN: 152004 Hom.: 15486 Cov.: 33

Gnomad AFR AF: 0.346

Gnomad AMI AF: 0.678

Gnomad AMR AF: 0.492

Gnomad ASJ AF: 0.433

Gnomad EAS AF: 0.553

Gnomad SAS AF: 0.402

Gnomad FIN AF: 0.467

Gnomad MID AF: 0.415

Gnomad NFE AF: 0.486

Gnomad OTH AF: 0.433

GnomAD4 exome AF: 0.470 AC: 38088 AN: 80972 Hom.: 9073 Cov.: 0 AF XY: 0.470 AC XY: 17487 AN XY: 37208

Gnomad4 AFR exome AF: 0.342

Gnomad4 AMR exome AF: 0.501

Gnomad4 ASJ exome AF: 0.433

Gnomad4 EAS exome AF: 0.526

Gnomad4 SAS exome AF: 0.401

Gnomad4 FIN exome AF: 0.391

Gnomad4 NFE exome AF: 0.475

Gnomad4 OTH exome AF: 0.450

GnomAD4 genome AF: 0.446 AC: 67841 AN: 152122 Hom.: 15498 Cov.: 33 AF XY: 0.446 AC XY: 33177 AN XY: 74378

Gnomad4 AFR AF: 0.346

Gnomad4 AMR AF: 0.492

Gnomad4 ASJ AF: 0.433

Gnomad4 EAS AF: 0.553

Gnomad4 SAS AF: 0.402

Gnomad4 FIN AF: 0.467

Gnomad4 NFE AF: 0.486

Gnomad4 OTH AF: 0.430

Alfa AF: 0.346 Hom.: 1074

Bravo AF: 0.446

Asia WGS AF: 0.479 AC: 1668 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 12, 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

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.6
DANN	Benign	0.64

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: rs2654981; hg19: chr15-99505129;