rs45453791

Variant names:

• chr15-98957403-C-G
• rs45453791
• NM_000875.5:c.4065C>G

Your query was ambiguous. Multiple possible variants found:

• chr15-98957403-C-G
• chr15-98957403-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000875.5(IGF1R):​c.4065C>G​(p.Asn1355Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. N1355N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: IGF1R NM_000875.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.125
• Publications: 0 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]

SYNM-AS1 (HGNC:55421): (SYNM antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19930825).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGF1R	NM_000875.5	c.4065C>G	p.Asn1355Lys	missense_variant	Exon 21 of 21	ENST00000650285.1	NP_000866.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGF1R	ENST00000650285.1	c.4065C>G	p.Asn1355Lys	missense_variant	Exon 21 of 21		NM_000875.5	ENSP00000497069.1
IGF1R	ENST00000649865.1	c.4062C>G	p.Asn1354Lys	missense_variant	Exon 21 of 21			ENSP00000496919.1
SYNM-AS1	ENST00000559468.1	n.349-3015G>C		intron_variant	Intron 3 of 3	4
IGF1R	ENST00000558751.1	n.*111C>G		downstream_gene_variant		4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jun 13, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.80	D;.;D;.
Eigen	Benign	-0.046
Eigen_PC	Benign	-0.093
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.83	.;.;T;T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.20	T;T;T;T
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Uncertain	2.3	M;.;M;.
PhyloP100		-0.13
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.5	.;.;D;D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0030	.;.;D;D
Sift4G	Uncertain	0.0090	.;.;D;D
Polyphen		0.90	P;B;P;B
Vest4		0.22, 0.22
MutPred		0.32		Gain of methylation at N1355 (P = 0.0098);.;Gain of methylation at N1355 (P = 0.0098);.;
MVP		0.80
MPC		0.21
ClinPred		0.98	D
GERP RS		0.62
Varity_R		0.51
gMVP		0.42
Mutation Taster		=21/79	disease causing

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: rs45453791; hg19: chr15-99500632;