rs28674628

Positions:

• chr15-98962599-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000875.5(IGF1R):​c.*5157A>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 0.0182 in 233,648 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.018 (27 hom., cov: 33)
  • Exomes 𝑓: 0.018 (21 hom.)
• Consequence: IGF1R NM_000875.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.219

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=-0.68).
• BP6: Variant 15-98962599-A-G is Benign according to our data. Variant chr15-98962599-A-G is described in ClinVar as [Benign]. Clinvar id is 885318.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0183 (2791/152178) while in subpopulation AFR AF= 0.0224 (928/41506). AF 95% confidence interval is 0.0212. There are 27 homozygotes in gnomad4. There are 1343 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 27 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IGF1R	NM_000875.5	c.*5157A>G		3_prime_UTR_variant	21/21	ENST00000650285.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGF1R	ENST00000650285.1	c.*5157A>G		3_prime_UTR_variant	21/21		NM_000875.5	P4
SYNM-AS1	ENST00000559468.1	n.348+3390T>C		intron_variant, non_coding_transcript_variant		4
IGF1R	ENST00000649865.1	c.*5157A>G		3_prime_UTR_variant	21/21			A1

Frequencies

GnomAD3 genomes AF: 0.0184 AC: 2795 AN: 152060 Hom.: 27 Cov.: 33

Gnomad AFR AF: 0.0224

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0155

Gnomad ASJ AF: 0.0260

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00934

Gnomad FIN AF: 0.0169

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0183

Gnomad OTH AF: 0.0253

GnomAD4 exome AF: 0.0180 AC: 1470 AN: 81470 Hom.: 21 Cov.: 0 AF XY: 0.0191 AC XY: 716 AN XY: 37540

Gnomad4 AFR exome AF: 0.0254

Gnomad4 AMR exome AF: 0.0144

Gnomad4 ASJ exome AF: 0.0287

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00855

Gnomad4 FIN exome AF: 0.0144

Gnomad4 NFE exome AF: 0.0201

Gnomad4 OTH exome AF: 0.0217

GnomAD4 genome AF: 0.0183 AC: 2791 AN: 152178 Hom.: 27 Cov.: 33 AF XY: 0.0180 AC XY: 1343 AN XY: 74418

Gnomad4 AFR AF: 0.0224

Gnomad4 AMR AF: 0.0155

Gnomad4 ASJ AF: 0.0260

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.00894

Gnomad4 FIN AF: 0.0169

Gnomad4 NFE AF: 0.0183

Gnomad4 OTH AF: 0.0255

Alfa AF: 0.0201 Hom.: 5

Bravo AF: 0.0186

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

Significance: 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

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	5.0
DANN	Benign	0.61

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: rs28674628; hg19: chr15-99505828;