15-98934996-G-A

Variant names:

• chr15-98934996-G-A
• rs2229765
• NM_000875.5:c.3129G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000875.5(IGF1R):​c.3129G>A​(p.Glu1043Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.429 in 1,613,534 control chromosomes in the GnomAD database, including 151,538 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (11963 hom., cov: 31)
  • Exomes 𝑓: 0.43 (139575 hom.)
• Consequence: IGF1R NM_000875.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.148
• Publications: 108 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, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 15-98934996-G-A is Benign according to our data. Variant chr15-98934996-G-A is described in ClinVar as Benign. ClinVar VariationId is 194610.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.148 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.448 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGF1R	NM_000875.5	MANE Select	c.3129G>A	p.Glu1043Glu	synonymous	Exon 16 of 21	NP_000866.1	P08069
	IGF1R	NM_001291858.2		c.3126G>A	p.Glu1042Glu	synonymous	Exon 16 of 21	NP_001278787.1	C9J5X1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGF1R	ENST00000650285.1	MANE Select	c.3129G>A	p.Glu1043Glu	synonymous	Exon 16 of 21	ENSP00000497069.1	P08069
	IGF1R	ENST00000560972.1	TSL:1	n.260-320G>A		intron	N/A
	IGF1R	ENST00000649865.1		c.3126G>A	p.Glu1042Glu	synonymous	Exon 16 of 21	ENSP00000496919.1	C9J5X1

Frequencies

GnomAD3 genomes AF: 0.391 AC: 59377 AN: 151908 Hom.: 11959 Cov.: 31

Gnomad AFR AF: 0.298

Gnomad AMI AF: 0.398

Gnomad AMR AF: 0.379

Gnomad ASJ AF: 0.465

Gnomad EAS AF: 0.338

Gnomad SAS AF: 0.315

Gnomad FIN AF: 0.413

Gnomad MID AF: 0.396

Gnomad NFE AF: 0.452

Gnomad OTH AF: 0.384

GnomAD2 exomes AF: 0.397 AC: 99711 AN: 251348 AF XY: 0.398

Gnomad AFR exome AF: 0.294

Gnomad AMR exome AF: 0.335

Gnomad ASJ exome AF: 0.476

Gnomad EAS exome AF: 0.351

Gnomad FIN exome AF: 0.413

Gnomad NFE exome AF: 0.452

Gnomad OTH exome AF: 0.412

GnomAD4 exome AF: 0.433 AC: 632746 AN: 1461508 Hom.: 139575 Cov.: 46 AF XY: 0.430 AC XY: 312426 AN XY: 727054

African (AFR) AF: 0.295 AC: 9868 AN: 33476

American (AMR) AF: 0.343 AC: 15336 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.473 AC: 12358 AN: 26132

East Asian (EAS) AF: 0.311 AC: 12351 AN: 39696

South Asian (SAS) AF: 0.308 AC: 26585 AN: 86252

European-Finnish (FIN) AF: 0.422 AC: 22523 AN: 53412

Middle Eastern (MID) AF: 0.362 AC: 2088 AN: 5764

European-Non Finnish (NFE) AF: 0.456 AC: 506779 AN: 1111668

Other (OTH) AF: 0.412 AC: 24858 AN: 60390

GnomAD4 genome AF: 0.391 AC: 59409 AN: 152026 Hom.: 11963 Cov.: 31 AF XY: 0.388 AC XY: 28824 AN XY: 74304

African (AFR) AF: 0.299 AC: 12375 AN: 41454

American (AMR) AF: 0.379 AC: 5790 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.465 AC: 1611 AN: 3468

East Asian (EAS) AF: 0.338 AC: 1741 AN: 5156

South Asian (SAS) AF: 0.316 AC: 1517 AN: 4806

European-Finnish (FIN) AF: 0.413 AC: 4365 AN: 10566

Middle Eastern (MID) AF: 0.405 AC: 119 AN: 294

European-Non Finnish (NFE) AF: 0.452 AC: 30730 AN: 67976

Other (OTH) AF: 0.379 AC: 799 AN: 2108

Alfa AF: 0.423 Hom.: 33963

Bravo AF: 0.385

Asia WGS AF: 0.322 AC: 1120 AN: 3478

EpiCase AF: 0.429

EpiControl AF: 0.438

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	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	-0.52
CADD	Benign	1.2
DANN	Benign	0.50
PhyloP100		-0.15
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: rs2229765; hg19: chr15-99478225; COSMIC: COSV51291816;