rs117440569

Variant names:

• chr15-98908773-A-G
• rs117440569
• NM_000875.5:c.1336A>G

Your query was ambiguous. Multiple possible variants found:

• chr15-98908773-A-G
• chr15-98908773-A-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000875.5(IGF1R):​c.1336A>G​(p.Met446Val) variant causes a missense change. The variant allele was found at a frequency of 0.00138 in 1,614,194 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M446I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0015 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (2 hom.)
• Consequence: IGF1R NM_000875.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: 5.36
• 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, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011108369).
• BP6: Variant 15-98908773-A-G is Benign according to our data. Variant chr15-98908773-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 282332.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00147 (224/152350) while in subpopulation AMR AF = 0.00314 (48/15304). AF 95% confidence interval is 0.00243. There are 3 homozygotes in GnomAd4. There are 100 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.1336A>G	p.Met446Val	missense	Exon 6 of 21	NP_000866.1	P08069
	IGF1R	NM_001291858.2		c.1336A>G	p.Met446Val	missense	Exon 6 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.1336A>G	p.Met446Val	missense	Exon 6 of 21	ENSP00000497069.1	P08069
	IGF1R	ENST00000559925.5	TSL:1	n.1336A>G		non_coding_transcript_exon	Exon 6 of 10
	IGF1R	ENST00000649865.1		c.1336A>G	p.Met446Val	missense	Exon 6 of 21	ENSP00000496919.1	C9J5X1

Frequencies

GnomAD3 genomes AF: 0.00147 AC: 224 AN: 152232 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000675

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00194

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00105 AC: 264 AN: 251244 AF XY: 0.00102

Gnomad AFR exome AF: 0.000616

Gnomad AMR exome AF: 0.000810

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.00171

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.00137 AC: 2000 AN: 1461844 Hom.: 2 Cov.: 32 AF XY: 0.00130 AC XY: 945 AN XY: 727224

African (AFR) AF: 0.000418 AC: 14 AN: 33480

American (AMR) AF: 0.00119 AC: 53 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

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

South Asian (SAS) AF: 0.000707 AC: 61 AN: 86250

European-Finnish (FIN) AF: 0.000749 AC: 40 AN: 53416

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.00156 AC: 1730 AN: 1111982

Other (OTH) AF: 0.00156 AC: 94 AN: 60392

GnomAD4 genome AF: 0.00147 AC: 224 AN: 152350 Hom.: 3 Cov.: 33 AF XY: 0.00134 AC XY: 100 AN XY: 74508

African (AFR) AF: 0.000673 AC: 28 AN: 41582

American (AMR) AF: 0.00314 AC: 48 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00103 AC: 5 AN: 4834

European-Finnish (FIN) AF: 0.000659 AC: 7 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00194 AC: 132 AN: 68032

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00148 Hom.: 2

Bravo AF: 0.00187

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000683 AC: 3

ESP6500EA AF: 0.00279 AC: 24

ExAC AF: 0.00117 AC: 142

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00153

EpiControl AF: 0.00130

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	5	not provided (6)
-	-	2	not specified (2)
-	-	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
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.54	D
Eigen	Benign	-0.082
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	-0.38	N
PhyloP100		5.4
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.21
Sift	Benign	0.17	T
Sift4G	Benign	0.38	T
Polyphen		0.0050	B
Vest4		0.53
MVP		0.78
MPC		0.64
ClinPred		0.022	T
GERP RS		5.8
Varity_R		0.25
gMVP		0.53
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs117440569; hg19: chr15-99452002;