15-98916049-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_000875.5(IGF1R):​c.1914C>A​(p.Asn638Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N638N) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Consequence

IGF1R
NM_000875.5 missense

Scores

7
9
3

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0460
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), IGF1R. . Trascript score misZ: 4.6449 (greater than threshold 3.09). The gene has 12 curated pathogenic missense variants (we use a threshold of 10). The gene has 19 curated benign missense variants. GenCC has associacion of the gene with growth delay due to insulin-like growth factor I resistance.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
IGF1RNM_000875.5 linkc.1914C>A p.Asn638Lys missense_variant 9/21 ENST00000650285.1 NP_000866.1 P08069

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
IGF1RENST00000650285.1 linkc.1914C>A p.Asn638Lys missense_variant 9/21 NM_000875.5 ENSP00000497069.1 P08069
IGF1RENST00000559925.5 linkn.1914C>A non_coding_transcript_exon_variant 9/101
IGF1RENST00000649865.1 linkc.1914C>A p.Asn638Lys missense_variant 9/21 ENSP00000496919.1 C9J5X1
IGF1RENST00000560144.1 linkn.142C>A non_coding_transcript_exon_variant 2/43 ENSP00000456950.1 H3BSZ8

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Uncertain
0.064
T
BayesDel_noAF
Benign
-0.15
CADD
Benign
18
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.89
D;.;D;.
Eigen
Uncertain
0.20
Eigen_PC
Benign
0.072
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Uncertain
0.92
.;.;D;D
M_CAP
Pathogenic
0.39
D
MetaRNN
Uncertain
0.63
D;D;D;D
MetaSVM
Uncertain
0.040
D
MutationAssessor
Pathogenic
3.2
M;.;M;.
PrimateAI
Uncertain
0.61
T
PROVEAN
Pathogenic
-5.3
.;.;D;D
REVEL
Pathogenic
0.65
Sift
Pathogenic
0.0
.;.;D;D
Sift4G
Uncertain
0.0020
.;.;D;D
Polyphen
1.0
D;D;D;D
Vest4
0.94, 0.93
MutPred
0.57
Gain of methylation at N638 (P = 0.0024);Gain of methylation at N638 (P = 0.0024);Gain of methylation at N638 (P = 0.0024);Gain of methylation at N638 (P = 0.0024);
MVP
0.94
MPC
1.7
ClinPred
0.99
D
GERP RS
1.1
Varity_R
0.83
gMVP
0.97

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.13
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-99459278; API