NM_000875.5:c.*3129G>T

Variant names:

• chr15-98960571-G-T
• rs2016347
• NM_000875.5:c.*3129G>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.*3129G>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 0.478 in 233,420 control chromosomes in the GnomAD database, including 27,453 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (16545 hom., cov: 33)
  • Exomes 𝑓: 0.52 (10908 hom.)
• Consequence: IGF1R NM_000875.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.529
• Publications: 38 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=-0.81).
• BP6: Variant 15-98960571-G-T is Benign according to our data. Variant chr15-98960571-G-T is described in ClinVar as Benign. ClinVar VariationId is 317546.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.592 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000875.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGF1R	NM_000875.5	MANE Select	c.*3129G>T		3_prime_UTR	Exon 21 of 21	NP_000866.1
	IGF1R	NM_001291858.2		c.*3129G>T		3_prime_UTR	Exon 21 of 21	NP_001278787.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGF1R	ENST00000650285.1	MANE Select	c.*3129G>T		3_prime_UTR	Exon 21 of 21	ENSP00000497069.1
	IGF1R	ENST00000649865.1		c.*3129G>T		3_prime_UTR	Exon 21 of 21	ENSP00000496919.1
	SYNM-AS1	ENST00000559468.1	TSL:4	n.348+5418C>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.458 AC: 69631 AN: 151992 Hom.: 16535 Cov.: 33

Gnomad AFR AF: 0.324

Gnomad AMI AF: 0.277

Gnomad AMR AF: 0.455

Gnomad ASJ AF: 0.521

Gnomad EAS AF: 0.526

Gnomad SAS AF: 0.610

Gnomad FIN AF: 0.528

Gnomad MID AF: 0.494

Gnomad NFE AF: 0.512

Gnomad OTH AF: 0.483

GnomAD4 exome AF: 0.515 AC: 41907 AN: 81310 Hom.: 10908 Cov.: 0 AF XY: 0.518 AC XY: 19416 AN XY: 37478

African (AFR) AF: 0.329 AC: 1283 AN: 3904

American (AMR) AF: 0.457 AC: 1141 AN: 2498

Ashkenazi Jewish (ASJ) AF: 0.521 AC: 2673 AN: 5126

East Asian (EAS) AF: 0.579 AC: 6612 AN: 11418

South Asian (SAS) AF: 0.630 AC: 447 AN: 710

European-Finnish (FIN) AF: 0.544 AC: 37 AN: 68

Middle Eastern (MID) AF: 0.520 AC: 257 AN: 494

European-Non Finnish (NFE) AF: 0.518 AC: 26044 AN: 50304

Other (OTH) AF: 0.503 AC: 3413 AN: 6788

GnomAD4 genome AF: 0.458 AC: 69678 AN: 152110 Hom.: 16545 Cov.: 33 AF XY: 0.461 AC XY: 34277 AN XY: 74342

African (AFR) AF: 0.324 AC: 13473 AN: 41528

American (AMR) AF: 0.455 AC: 6952 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.521 AC: 1807 AN: 3470

East Asian (EAS) AF: 0.526 AC: 2708 AN: 5144

South Asian (SAS) AF: 0.610 AC: 2938 AN: 4816

European-Finnish (FIN) AF: 0.528 AC: 5588 AN: 10582

Middle Eastern (MID) AF: 0.497 AC: 146 AN: 294

European-Non Finnish (NFE) AF: 0.512 AC: 34788 AN: 67968

Other (OTH) AF: 0.486 AC: 1026 AN: 2110

Alfa AF: 0.487 Hom.: 35315

Bravo AF: 0.444

Asia WGS AF: 0.540 AC: 1875 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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.5
DANN	Benign	0.61
PhyloP100		0.53
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2016347; hg19: chr15-99503800; COSMIC: COSV51410426; COSMIC: COSV51410426;