rs34102392

Variant names:

• chr15-98957350-G-A
• rs34102392
• NM_000875.5:c.4012G>A

Your query was ambiguous. Multiple possible variants found:

• chr15-98957350-G-A
• chr15-98957350-G-C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BS1_Supporting

The NM_000875.5(IGF1R):​c.4012G>A​(p.Ala1338Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000023 in 1,612,008 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1338P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: IGF1R NM_000875.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.93
• Publications: 7 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: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15406719).
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.0000219 (32/1459660) while in subpopulation EAS AF = 0.000177 (7/39640). AF 95% confidence interval is 0.0000821. There are 0 homozygotes in GnomAdExome4. There are 13 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.4012G>A	p.Ala1338Thr	missense	Exon 21 of 21	NP_000866.1	P08069
	IGF1R	NM_001291858.2		c.4009G>A	p.Ala1337Thr	missense	Exon 21 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.4012G>A	p.Ala1338Thr	missense	Exon 21 of 21	ENSP00000497069.1	P08069
	IGF1R	ENST00000649865.1		c.4009G>A	p.Ala1337Thr	missense	Exon 21 of 21	ENSP00000496919.1	C9J5X1
	SYNM-AS1	ENST00000559468.1	TSL:4	n.349-2962C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152230 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000720 AC: 18 AN: 249892 AF XY: 0.0000665

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000600

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000887

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000219 AC: 32 AN: 1459660 Hom.: 0 Cov.: 33 AF XY: 0.0000179 AC XY: 13 AN XY: 725780

African (AFR) AF: 0.000149 AC: 5 AN: 33446

American (AMR) AF: 0.0000448 AC: 2 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

East Asian (EAS) AF: 0.000177 AC: 7 AN: 39640

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86194

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52856

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1110654

Other (OTH) AF: 0.00 AC: 0 AN: 60336

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152348 Hom.: 0 Cov.: 33 AF XY: 0.0000268 AC XY: 2 AN XY: 74488

African (AFR) AF: 0.0000721 AC: 3 AN: 41590

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000453

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000494 AC: 6

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.85	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.15	T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	1.4	L
PhyloP100		3.9
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.28	N
REVEL	Benign	0.29
Sift	Benign	0.17	T
Sift4G	Benign	0.25	T
Polyphen		0.22	B
Vest4		0.065
MVP		0.60
MPC		0.25
ClinPred		0.082	T
GERP RS		5.7
Varity_R		0.042
gMVP		0.64
Mutation Taster		=81/19	polymorphism

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: rs34102392; hg19: chr15-99500579; COSMIC: COSV51321408; COSMIC: COSV51321408;