NM_000875.5:c.3907G>C

Variant names:

• chr15-98957245-G-C
• rs45475702
• NM_000875.5:c.3907G>C

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.3907G>C​(p.Val1303Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1303I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: IGF1R NM_000875.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.40
• Publications: 5 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=0.098724514).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGF1R	NM_000875.5	c.3907G>C	p.Val1303Leu	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.3907G>C	p.Val1303Leu	missense_variant	Exon 21 of 21		NM_000875.5	ENSP00000497069.1
IGF1R	ENST00000649865.1	c.3904G>C	p.Val1302Leu	missense_variant	Exon 21 of 21			ENSP00000496919.1
IGF1R	ENST00000558751.1	n.501G>C		non_coding_transcript_exon_variant	Exon 2 of 2	4
SYNM-AS1	ENST00000559468.1	n.349-2857C>G		intron_variant	Intron 3 of 3	4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.47	T;.;T;.
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.0061
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	1.0	.;.;D;D
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.099	T;T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.4	L;.;L;.
PhyloP100		4.4
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.1	.;.;N;N
REVEL	Benign	0.17
Sift	Benign	0.083	.;.;T;T
Sift4G	Benign	0.64	.;.;T;T
Polyphen		0.027	B;B;B;B
Vest4		0.093, 0.088
MutPred		0.16		Gain of helix (P = 0.0854);.;Gain of helix (P = 0.0854);.;
MVP		0.72
MPC		0.059
ClinPred		0.51	D
GERP RS		3.4
Varity_R		0.053
gMVP		0.34

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: rs45475702; hg19: chr15-99500474;