12-102475822-G-T

Variant names:

• chr12-102475822-G-T
• rs5742620
• NM_000618.5:c.64-23C>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BS1 BS2

The NM_000618.5(IGF1):​c.64-23C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0288 in 1,602,894 control chromosomes in the GnomAD database, including 759 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.032 (99 hom., cov: 32)
  • Exomes 𝑓: 0.028 (660 hom.)
• Consequence: IGF1 NM_000618.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.11
• Publications: 12 publications found

Genes affected

IGF1 (HGNC:5464): (insulin like growth factor 1) The protein encoded by this gene is similar to insulin in function and structure and is a member of a family of proteins involved in mediating growth and development. The encoded protein is processed from a precursor, bound by a specific receptor, and secreted. Defects in this gene are a cause of insulin-like growth factor I deficiency. Alternative splicing results in multiple transcript variants encoding different isoforms that may undergo similar processing to generate mature protein. [provided by RefSeq, Sep 2015]

LINC02456 (HGNC:53389): (long intergenic non-protein coding RNA 2456)

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.2).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0325 (4943/152216) while in subpopulation AFR AF = 0.0402 (1668/41530). AF 95% confidence interval is 0.0386. There are 99 homozygotes in GnomAd4. There are 2407 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 99 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000618.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGF1	NM_000618.5	MANE Select	c.64-23C>A		intron	N/A	NP_000609.1
	IGF1	NM_001111285.3		c.64-23C>A		intron	N/A	NP_001104755.1
	IGF1	NM_001414005.1		c.64-23C>A		intron	N/A	NP_001400934.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGF1	ENST00000337514.11	TSL:1 MANE Select	c.64-23C>A		intron	N/A	ENSP00000337612.7
	IGF1	ENST00000307046.8	TSL:1	c.64-23C>A		intron	N/A	ENSP00000302665.8
	IGF1	ENST00000424202.6	TSL:1	c.16-23C>A		intron	N/A	ENSP00000416811.2

Frequencies

GnomAD3 genomes AF: 0.0325 AC: 4936 AN: 152098 Hom.: 98 Cov.: 32

Gnomad AFR AF: 0.0401

Gnomad AMI AF: 0.0965

Gnomad AMR AF: 0.0285

Gnomad ASJ AF: 0.0242

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00540

Gnomad FIN AF: 0.0392

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0318

Gnomad OTH AF: 0.0287

GnomAD2 exomes AF: 0.0248 AC: 5677 AN: 229324 AF XY: 0.0243

Gnomad AFR exome AF: 0.0419

Gnomad AMR exome AF: 0.0216

Gnomad ASJ exome AF: 0.0197

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0431

Gnomad NFE exome AF: 0.0298

Gnomad OTH exome AF: 0.0272

GnomAD4 exome AF: 0.0285 AC: 41291 AN: 1450678 Hom.: 660 Cov.: 31 AF XY: 0.0277 AC XY: 19955 AN XY: 720598

African (AFR) AF: 0.0386 AC: 1281 AN: 33182

American (AMR) AF: 0.0230 AC: 989 AN: 42976

Ashkenazi Jewish (ASJ) AF: 0.0220 AC: 569 AN: 25858

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39234

South Asian (SAS) AF: 0.00467 AC: 396 AN: 84722

European-Finnish (FIN) AF: 0.0445 AC: 2354 AN: 52852

Middle Eastern (MID) AF: 0.0145 AC: 83 AN: 5728

European-Non Finnish (NFE) AF: 0.0308 AC: 34015 AN: 1106120

Other (OTH) AF: 0.0267 AC: 1603 AN: 60006

GnomAD4 genome AF: 0.0325 AC: 4943 AN: 152216 Hom.: 99 Cov.: 32 AF XY: 0.0323 AC XY: 2407 AN XY: 74424

African (AFR) AF: 0.0402 AC: 1668 AN: 41530

American (AMR) AF: 0.0285 AC: 436 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0242 AC: 84 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00561 AC: 27 AN: 4812

European-Finnish (FIN) AF: 0.0392 AC: 416 AN: 10606

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0318 AC: 2160 AN: 68006

Other (OTH) AF: 0.0284 AC: 60 AN: 2112

Alfa AF: 0.0302 Hom.: 103

Bravo AF: 0.0324

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.20
CADD	Benign	17
DANN	Benign	0.86
PhyloP100		3.1
Mutation Taster		=97/3	polymorphism (auto)

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: rs5742620; hg19: chr12-102869600; COSMIC: COSV61032916;