rs6221

Variant names:

• chr12-102397237-A-C
• rs6221
• NM_000618.5:c.*5270T>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000618.5(IGF1):​c.*5270T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00777 in 162,038 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0082 (18 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (0 hom.)
• Consequence: IGF1 NM_000618.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.455
• Publications: 2 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 12-102397237-A-C is Benign according to our data. Variant chr12-102397237-A-C is described in ClinVar as Benign. ClinVar VariationId is 306843.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00819 (1245/152056) while in subpopulation AFR AF = 0.0285 (1181/41494). AF 95% confidence interval is 0.0271. There are 18 homozygotes in GnomAd4. There are 582 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 18 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGF1	NM_000618.5	MANE Select	c.*5270T>G		3_prime_UTR	Exon 4 of 4	NP_000609.1	Q5U743
	IGF1	NM_001111283.3		c.*5304T>G		3_prime_UTR	Exon 5 of 5	NP_001104753.1	P05019-4
	IGF1	NM_001414007.1		c.*5270T>G		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.*5270T>G		3_prime_UTR	Exon 4 of 4	ENSP00000337612.7	P05019-2
	HELLPAR	ENST00000626826.1	TSL:6	n.199653A>C		non_coding_transcript_exon	Exon 1 of 1
	LINC02456	ENST00000635615.1	TSL:5	n.450-25834A>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00819 AC: 1244 AN: 151938 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.0285

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00210

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00526

GnomAD4 exome AF: 0.00140 AC: 14 AN: 9982 Hom.: 0 Cov.: 0 AF XY: 0.00139 AC XY: 7 AN XY: 5052

African (AFR) AF: 0.0242 AC: 11 AN: 454

American (AMR) AF: 0.00365 AC: 1 AN: 274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 490

East Asian (EAS) AF: 0.00 AC: 0 AN: 714

South Asian (SAS) AF: 0.00 AC: 0 AN: 74

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 288

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 56

European-Non Finnish (NFE) AF: 0.000146 AC: 1 AN: 6868

Other (OTH) AF: 0.00131 AC: 1 AN: 764

GnomAD4 genome AF: 0.00819 AC: 1245 AN: 152056 Hom.: 18 Cov.: 32 AF XY: 0.00783 AC XY: 582 AN XY: 74348

African (AFR) AF: 0.0285 AC: 1181 AN: 41494

American (AMR) AF: 0.00210 AC: 32 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10578

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

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 67958

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00491 Hom.: 1

Bravo AF: 0.00949

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

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	-0.90
CADD	Benign	0.34
DANN	Benign	0.36
PhyloP100		-0.46
Mutation Taster		=100/0	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: rs6221; hg19: chr12-102791015;