15-98958352-C-T

Variant names:

• chr15-98958352-C-T
• rs702497
• NM_000875.5:c.*910C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.286
• Publications: 16 publications found

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

Our verdict: Benign. The variant received -20 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 VariationId is 317492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.227 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGF1R	NM_000875.5	c.*910C>T		3_prime_UTR_variant	Exon 21 of 21	ENST00000650285.1	NP_000866.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGF1R	ENST00000650285.1	c.*910C>T		3_prime_UTR_variant	Exon 21 of 21		NM_000875.5	ENSP00000497069.1
IGF1R	ENST00000649865.1	c.*910C>T		3_prime_UTR_variant	Exon 21 of 21			ENSP00000496919.1
SYNM-AS1	ENST00000559468.1	n.349-3964G>A		intron_variant	Intron 3 of 3	4

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

African (AFR) AF: 0.138 AC: 444 AN: 3226

American (AMR) AF: 0.160 AC: 332 AN: 2074

Ashkenazi Jewish (ASJ) AF: 0.144 AC: 640 AN: 4442

East Asian (EAS) AF: 0.0233 AC: 245 AN: 10536

South Asian (SAS) AF: 0.0641 AC: 39 AN: 608

European-Finnish (FIN) AF: 0.250 AC: 15 AN: 60

Middle Eastern (MID) AF: 0.153 AC: 66 AN: 432

European-Non Finnish (NFE) AF: 0.198 AC: 8396 AN: 42366

Other (OTH) AF: 0.165 AC: 956 AN: 5800

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

African (AFR) AF: 0.157 AC: 6455 AN: 41124

American (AMR) AF: 0.183 AC: 2787 AN: 15190

Ashkenazi Jewish (ASJ) AF: 0.166 AC: 577 AN: 3466

East Asian (EAS) AF: 0.0240 AC: 123 AN: 5118

South Asian (SAS) AF: 0.0709 AC: 338 AN: 4764

European-Finnish (FIN) AF: 0.249 AC: 2589 AN: 10390

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.230 AC: 15585 AN: 67768

Other (OTH) AF: 0.189 AC: 397 AN: 2100

Alfa AF: 0.213 Hom.: 10510

Bravo AF: 0.190

Asia WGS AF: 0.0830 AC: 290 AN: 3478

ClinVar

Significance: Likely 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

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.9
DANN	Benign	0.59
PhyloP100		0.29
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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