Genetic Variant IGF1R:p.Ala701Ser (chr15-98916776-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000875.5(IGF1R):c.2101G>T(p.Ala701Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000752 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. A701T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

IGF1R
NM_000875.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.38

Publications

6 publications found

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]

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, Labcorp Genetics (formerly Invitae), Orphanet

IGF1R links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.12901697).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGF1R	NM_000875.5 link	c.2101G>T	p.Ala701Ser	missense_variant	Exon 10 of 21	ENST00000650285.1	NP_000866.1	P08069

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGF1R	ENST00000650285.1 link	c.2101G>T	p.Ala701Ser	missense_variant	Exon 10 of 21		NM_000875.5	ENSP00000497069.1		P08069

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000796

AC:

AN:

251196

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000752

AC:

AN:

1461838

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000899

AC:

AN:

1111986

Other (OTH)

AF:

0.00

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.40

T;.;T;.

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.33

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.89

.;.;D;D

M_CAP

Benign

0.0098

MetaRNN

Benign

0.13

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

L;.;L;.

PhyloP100

3.4

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.44

.;.;N;N

REVEL

Benign

0.050

Sift

Benign

0.71

.;.;T;T

Sift4G

Benign

0.74

.;.;T;T

Polyphen

0.059

B;P;B;P

Vest4

0.17, 0.20

MutPred

0.16

Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);

MVP

0.55

MPC

0.71

ClinPred

0.22

GERP RS

3.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.11

gMVP

0.32

Mutation Taster

=91/9

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over