rs6213

chr12-102417846-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000307046.8(IGF1):c.560C>A(p.Ala187Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00163 in 1,613,700 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0084 (21 hom., cov: 32)
  • Exomes 𝑓: 0.00093 (26 hom.)
• Consequence: IGF1 ENST00000307046.8 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.927

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

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002417773).
• BP6: Variant 12-102417846-G-T is Benign according to our data. Variant chr12-102417846-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 376935.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-102417846-G-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00842 (1281/152108) while in subpopulation AFR AF= 0.0292 (1213/41472). AF 95% confidence interval is 0.0279. There are 21 homozygotes in gnomad4. There are 599 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IGF1	NM_000618.5	c.402+1663C>A		intron_variant		ENST00000337514.11
LINC02456	XR_007063427.1	n.6690+3774G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGF1	ENST00000337514.11	c.402+1663C>A		intron_variant		1	NM_000618.5	P1
LINC02456	ENST00000704346.1	n.1067-5225G>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00842 AC: 1279 AN: 151990 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.0293

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

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: 0.00669

GnomAD3 exomes AF: 0.00205 AC: 509 AN: 248594 Hom.: 7 AF XY: 0.00154 AC XY: 208 AN XY: 135078

Gnomad AFR exome AF: 0.0283

Gnomad AMR exome AF: 0.000987

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000178

Gnomad OTH exome AF: 0.00215

GnomAD4 exome AF: 0.000925 AC: 1352 AN: 1461592 Hom.: 26 Cov.: 32 AF XY: 0.000847 AC XY: 616 AN XY: 727082

Gnomad4 AFR exome AF: 0.0307

Gnomad4 AMR exome AF: 0.00119

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000107

Gnomad4 OTH exome AF: 0.00204

GnomAD4 genome AF: 0.00842 AC: 1281 AN: 152108 Hom.: 21 Cov.: 32 AF XY: 0.00806 AC XY: 599 AN XY: 74356

Gnomad4 AFR AF: 0.0292

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00203 Hom.: 4

Bravo AF: 0.00973

ESP6500AA AF: 0.0220 AC: 69

ESP6500EA AF: 0.000140 AC: 1

ExAC AF: 0.00247 AC: 298

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000296

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Jan 12, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.37	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	D;D;D;D;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.50	N
REVEL	Uncertain	0.32
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.026	D
Polyphen		0.0	B
Vest4		0.19
MVP		0.95
MPC		1.2
ClinPred		0.014	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		0.95
Varity_R		0.10

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

Publications

LitVar

Other links and lift over

dbSNP: rs6213; hg19: chr12-102811624;