12-102397058-C-T

Variant names:

• chr12-102397058-C-T
• rs569070910
• NM_000618.5:c.*5449G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_000618.5(IGF1):​c.*5449G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 366,040 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (1 hom.)
• Consequence: IGF1 NM_000618.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.766
• Publications: 0 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]

HELLPAR (HGNC:43984): (HELLP associated long non-coding RNA)

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

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.0017 (365/214200) while in subpopulation EAS AF = 0.0169 (347/20508). AF 95% confidence interval is 0.0155. There are 1 homozygotes in GnomAdExome4. There are 188 alleles in the male GnomAdExome4 subpopulation. Median coverage is 0. 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_000618.5. 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
	IGF1	NM_000618.5	MANE Select	c.*5449G>A		3_prime_UTR	Exon 4 of 4	NP_000609.1	Q5U743
	IGF1	NM_001111283.3		c.*5483G>A		3_prime_UTR	Exon 5 of 5	NP_001104753.1	P05019-4
	IGF1	NM_001414007.1		c.*5449G>A		3_prime_UTR	Exon 5 of 5	NP_001400936.1	Q5U743

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGF1	ENST00000337514.11	TSL:1 MANE Select	c.*5449G>A		3_prime_UTR	Exon 4 of 4	ENSP00000337612.7	P05019-2
	HELLPAR	ENST00000626826.1	TSL:6	n.199474C>T		non_coding_transcript_exon	Exon 1 of 1
	LINC02456	ENST00000635615.1	TSL:5	n.450-26013C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000198 AC: 30 AN: 151722 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00445

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000479

GnomAD4 exome AF: 0.00170 AC: 365 AN: 214200 Hom.: 1 Cov.: 0 AF XY: 0.00173 AC XY: 188 AN XY: 108774

African (AFR) AF: 0.00 AC: 0 AN: 6346

American (AMR) AF: 0.00 AC: 0 AN: 6368

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8170

East Asian (EAS) AF: 0.0169 AC: 347 AN: 20508

South Asian (SAS) AF: 0.00 AC: 0 AN: 1880

European-Finnish (FIN) AF: 0.0000582 AC: 1 AN: 17190

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1116

European-Non Finnish (NFE) AF: 0.0000867 AC: 12 AN: 138416

Other (OTH) AF: 0.000352 AC: 5 AN: 14206

GnomAD4 genome AF: 0.000191 AC: 29 AN: 151840 Hom.: 0 Cov.: 32 AF XY: 0.000189 AC XY: 14 AN XY: 74212

African (AFR) AF: 0.0000242 AC: 1 AN: 41398

American (AMR) AF: 0.00 AC: 0 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00446 AC: 23 AN: 5158

South Asian (SAS) AF: 0.000417 AC: 2 AN: 4798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10538

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

European-Non Finnish (NFE) AF: 0.0000442 AC: 3 AN: 67944

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Growth delay due to insulin-like growth factor type 1 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.2
DANN	Benign	0.26
PhyloP100		-0.77

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: rs569070910; hg19: chr12-102790836;