chr15-98962194-G-T

Variant names:

• chr15-98962194-G-T
• rs3743249
• NM_000875.5:c.*4752G>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.*4752G>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 0.327 in 233,090 control chromosomes in the GnomAD database, including 13,802 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (9971 hom., cov: 33)
  • Exomes 𝑓: 0.30 (3831 hom.)
• Consequence: IGF1R NM_000875.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.820
• 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=-0.83).
• BP6: Variant 15-98962194-G-T is Benign according to our data. Variant chr15-98962194-G-T is described in ClinVar as Benign. ClinVar VariationId is 317589.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.505 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.*4752G>T		3_prime_UTR	Exon 21 of 21	NP_000866.1
	IGF1R	NM_001291858.2		c.*4752G>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.*4752G>T		3_prime_UTR	Exon 21 of 21	ENSP00000497069.1
	IGF1R	ENST00000649865.1		c.*4752G>T		3_prime_UTR	Exon 21 of 21	ENSP00000496919.1
	SYNM-AS1	ENST00000559468.1	TSL:4	n.348+3795C>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.343 AC: 52126 AN: 151966 Hom.: 9949 Cov.: 33

Gnomad AFR AF: 0.510

Gnomad AMI AF: 0.419

Gnomad AMR AF: 0.366

Gnomad ASJ AF: 0.287

Gnomad EAS AF: 0.466

Gnomad SAS AF: 0.320

Gnomad FIN AF: 0.212

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.251

Gnomad OTH AF: 0.323

GnomAD4 exome AF: 0.297 AC: 24027 AN: 81006 Hom.: 3831 Cov.: 0 AF XY: 0.294 AC XY: 10949 AN XY: 37242

African (AFR) AF: 0.513 AC: 1996 AN: 3892

American (AMR) AF: 0.364 AC: 910 AN: 2500

Ashkenazi Jewish (ASJ) AF: 0.295 AC: 1512 AN: 5126

East Asian (EAS) AF: 0.399 AC: 4555 AN: 11402

South Asian (SAS) AF: 0.286 AC: 201 AN: 702

European-Finnish (FIN) AF: 0.194 AC: 12 AN: 62

Middle Eastern (MID) AF: 0.297 AC: 146 AN: 492

European-Non Finnish (NFE) AF: 0.252 AC: 12629 AN: 50058

Other (OTH) AF: 0.305 AC: 2066 AN: 6772

GnomAD4 genome AF: 0.343 AC: 52184 AN: 152084 Hom.: 9971 Cov.: 33 AF XY: 0.344 AC XY: 25601 AN XY: 74362

African (AFR) AF: 0.511 AC: 21179 AN: 41480

American (AMR) AF: 0.366 AC: 5599 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.287 AC: 996 AN: 3470

East Asian (EAS) AF: 0.466 AC: 2400 AN: 5154

South Asian (SAS) AF: 0.319 AC: 1542 AN: 4828

European-Finnish (FIN) AF: 0.212 AC: 2247 AN: 10588

Middle Eastern (MID) AF: 0.367 AC: 108 AN: 294

European-Non Finnish (NFE) AF: 0.251 AC: 17055 AN: 67968

Other (OTH) AF: 0.321 AC: 677 AN: 2110

Alfa AF: 0.283 Hom.: 12114

Bravo AF: 0.361

Asia WGS AF: 0.378 AC: 1313 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 13, 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	-0.83
CADD	Benign	3.7
DANN	Benign	0.61
PhyloP100		0.82
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: rs3743249; hg19: chr15-99505423;