rs28674628

Variant names:

• chr15-98962599-A-G
• rs28674628
• NM_000875.5:c.*5157A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.219
• Publications: 10 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=-0.68).
• BP6: Variant 15-98962599-A-G is Benign according to our data. Variant chr15-98962599-A-G is described in ClinVar as Benign. ClinVar VariationId is 885318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 27 AR,AD gene

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.*5157A>G		3_prime_UTR	Exon 21 of 21	NP_000866.1
	IGF1R	NM_001291858.2		c.*5157A>G		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.*5157A>G		3_prime_UTR	Exon 21 of 21	ENSP00000497069.1
	IGF1R	ENST00000649865.1		c.*5157A>G		3_prime_UTR	Exon 21 of 21	ENSP00000496919.1
	SYNM-AS1	ENST00000559468.1	TSL:4	n.348+3390T>C		intron	N/A

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

African (AFR) AF: 0.0254 AC: 99 AN: 3900

American (AMR) AF: 0.0144 AC: 36 AN: 2492

Ashkenazi Jewish (ASJ) AF: 0.0287 AC: 147 AN: 5124

East Asian (EAS) AF: 0.00 AC: 0 AN: 11398

South Asian (SAS) AF: 0.00855 AC: 6 AN: 702

European-Finnish (FIN) AF: 0.0144 AC: 7 AN: 486

Middle Eastern (MID) AF: 0.0407 AC: 20 AN: 492

European-Non Finnish (NFE) AF: 0.0201 AC: 1008 AN: 50092

Other (OTH) AF: 0.0217 AC: 147 AN: 6784

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

African (AFR) AF: 0.0224 AC: 928 AN: 41506

American (AMR) AF: 0.0155 AC: 237 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0260 AC: 90 AN: 3466

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5184

South Asian (SAS) AF: 0.00894 AC: 43 AN: 4812

European-Finnish (FIN) AF: 0.0169 AC: 179 AN: 10610

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0183 AC: 1243 AN: 67986

Other (OTH) AF: 0.0255 AC: 54 AN: 2114

Alfa AF: 0.0172 Hom.: 38

Bravo AF: 0.0186

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Growth delay due to insulin-like growth factor I resistance (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	5.0
DANN	Benign	0.61
PhyloP100		-0.22
Mutation Taster		=100/0	polymorphism

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: rs28674628; hg19: chr15-99505828;