rs36108138

Variant names:

• chr15-98911310-C-A
• rs36108138
• NM_000875.5:c.1463-5C>A

Your query was ambiguous. Multiple possible variants found:

• chr15-98911310-C-A
• chr15-98911310-C-T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_000875.5(IGF1R):​c.1463-5C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00224 in 1,614,078 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (35 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (36 hom.)
• Consequence: IGF1R NM_000875.5 splice_region, intron
• Scores: Splicing: ADA: 0.002908
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0270
• Publications: 4 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]

IGF1R Gene-Disease associations (from GenCC):

• growth delay due to insulin-like growth factor I resistance

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 15-98911310-C-A is Benign according to our data. Variant chr15-98911310-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 317447.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 = 0.0114 (1741/152222) while in subpopulation AFR AF = 0.0396 (1645/41532). AF 95% confidence interval is 0.038. There are 35 homozygotes in GnomAd4. There are 823 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 35 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGF1R	NM_000875.5	MANE Select	c.1463-5C>A		splice_region intron	N/A	NP_000866.1
	IGF1R	NM_001291858.2		c.1463-5C>A		splice_region intron	N/A	NP_001278787.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGF1R	ENST00000650285.1	MANE Select	c.1463-5C>A		splice_region intron	N/A	ENSP00000497069.1
	IGF1R	ENST00000559925.5	TSL:1	n.1463-5C>A		splice_region intron	N/A
	IGF1R	ENST00000649865.1		c.1463-5C>A		splice_region intron	N/A	ENSP00000496919.1

Frequencies

GnomAD3 genomes AF: 0.0114 AC: 1740 AN: 152104 Hom.: 35 Cov.: 32

Gnomad AFR AF: 0.0397

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00432

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00306 AC: 768 AN: 251388 AF XY: 0.00222

Gnomad AFR exome AF: 0.0409

Gnomad AMR exome AF: 0.00165

Gnomad ASJ exome AF: 0.00208

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00128 AC: 1871 AN: 1461856 Hom.: 36 Cov.: 32 AF XY: 0.00109 AC XY: 791 AN XY: 727232

African (AFR) AF: 0.0428 AC: 1433 AN: 33478

American (AMR) AF: 0.00192 AC: 86 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00176 AC: 46 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5768

European-Non Finnish (NFE) AF: 0.000116 AC: 129 AN: 1111988

Other (OTH) AF: 0.00258 AC: 156 AN: 60392

GnomAD4 genome AF: 0.0114 AC: 1741 AN: 152222 Hom.: 35 Cov.: 32 AF XY: 0.0111 AC XY: 823 AN XY: 74418

African (AFR) AF: 0.0396 AC: 1645 AN: 41532

American (AMR) AF: 0.00432 AC: 66 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68024

Other (OTH) AF: 0.00662 AC: 14 AN: 2114

Alfa AF: 0.00540 Hom.: 9

Bravo AF: 0.0131

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Growth delay due to insulin-like growth factor I resistance (1)
-	-	1	IGF1R-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	11
DANN	Benign	0.81
PhyloP100		-0.027
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0029
dbscSNV1_RF	Benign	0.13
SpliceAI score (max)		0.010		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: rs36108138; hg19: chr15-99454539;