15-98924602-C-T

Variant names:

• chr15-98924602-C-T
• rs56400113
• NM_000875.5:c.2700C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000875.5(IGF1R):​c.2700C>T​(p.Asn900Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00662 in 1,614,036 control chromosomes in the GnomAD database, including 90 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0072 (19 hom., cov: 33)
  • Exomes 𝑓: 0.0066 (71 hom.)
• Consequence: IGF1R NM_000875.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.15
• Publications: 8 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: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 15-98924602-C-T is Benign according to our data. Variant chr15-98924602-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 194185.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.15 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00715 (1089/152306) while in subpopulation NFE AF = 0.00779 (530/68028). AF 95% confidence interval is 0.00724. There are 19 homozygotes in GnomAd4. There are 625 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 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.2700C>T	p.Asn900Asn	synonymous	Exon 13 of 21	NP_000866.1
	IGF1R	NM_001291858.2		c.2700C>T	p.Asn900Asn	synonymous	Exon 13 of 21	NP_001278787.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGF1R	ENST00000650285.1	MANE Select	c.2700C>T	p.Asn900Asn	synonymous	Exon 13 of 21	ENSP00000497069.1
	IGF1R	ENST00000560972.1	TSL:1	n.3C>T		non_coding_transcript_exon	Exon 1 of 4
	IGF1R	ENST00000649865.1		c.2700C>T	p.Asn900Asn	synonymous	Exon 13 of 21	ENSP00000496919.1

Frequencies

GnomAD3 genomes AF: 0.00716 AC: 1090 AN: 152188 Hom.: 19 Cov.: 33

Gnomad AFR AF: 0.000845

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.0425

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00779

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00721 AC: 1814 AN: 251494 AF XY: 0.00727

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00168

Gnomad ASJ exome AF: 0.00496

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0375

Gnomad NFE exome AF: 0.00708

Gnomad OTH exome AF: 0.00717

GnomAD4 exome AF: 0.00656 AC: 9590 AN: 1461730 Hom.: 71 Cov.: 33 AF XY: 0.00650 AC XY: 4727 AN XY: 727176

African (AFR) AF: 0.000657 AC: 22 AN: 33478

American (AMR) AF: 0.00163 AC: 73 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00474 AC: 124 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00111 AC: 96 AN: 86256

European-Finnish (FIN) AF: 0.0339 AC: 1812 AN: 53418

Middle Eastern (MID) AF: 0.00485 AC: 28 AN: 5768

European-Non Finnish (NFE) AF: 0.00635 AC: 7055 AN: 1111864

Other (OTH) AF: 0.00628 AC: 379 AN: 60386

GnomAD4 genome AF: 0.00715 AC: 1089 AN: 152306 Hom.: 19 Cov.: 33 AF XY: 0.00839 AC XY: 625 AN XY: 74470

African (AFR) AF: 0.000842 AC: 35 AN: 41566

American (AMR) AF: 0.00196 AC: 30 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4824

European-Finnish (FIN) AF: 0.0425 AC: 451 AN: 10606

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00779 AC: 530 AN: 68028

Other (OTH) AF: 0.00568 AC: 12 AN: 2112

Alfa AF: 0.00622 Hom.: 5

Bravo AF: 0.00366

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00665

EpiControl AF: 0.00587

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	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	11
DANN	Benign	0.89
PhyloP100		1.1
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: rs56400113; hg19: chr15-99467831;