7-45916598-C-T

Position:

• chr7-45916598-C-T

Variant summary

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

The NM_000598.5(IGFBP3):​c.700G>A​(p.Gly234Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00158 in 1,613,226 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0085 (14 hom., cov: 32)
  • Exomes 𝑓: 0.00085 (15 hom.)
• Consequence: IGFBP3 NM_000598.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.64

Genes affected

IGFBP3 (HGNC:5472): (insulin like growth factor binding protein 3) This gene is a member of the insulin-like growth factor binding protein (IGFBP) family and encodes a protein with an IGFBP domain and a thyroglobulin type-I domain. The protein forms a ternary complex with insulin-like growth factor acid-labile subunit (IGFALS) and either insulin-like growth factor (IGF) I or II. In this form, it circulates in the plasma, prolonging the half-life of IGFs and altering their interaction with cell surface receptors. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

IGFBP3 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008894771).
• BP6: Variant 7-45916598-C-T is Benign according to our data. Variant chr7-45916598-C-T is described in ClinVar as [Benign]. Clinvar id is 716144.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00853 (1298/152216) while in subpopulation AFR AF= 0.03 (1244/41508). AF 95% confidence interval is 0.0286. There are 14 homozygotes in gnomad4. There are 604 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 14 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGFBP3	NM_000598.5	c.700G>A	p.Gly234Ser	missense_variant	3/5	ENST00000613132.5	NP_000589.2
IGFBP3	NM_001013398.2	c.718G>A	p.Gly240Ser	missense_variant	3/5		NP_001013416.1
IGFBP3	XM_047420325.1	c.700G>A	p.Gly234Ser	missense_variant	3/4		XP_047276281.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGFBP3	ENST00000613132.5	c.700G>A	p.Gly234Ser	missense_variant	3/5	5	NM_000598.5	ENSP00000477772.2

Frequencies

GnomAD3 genomes AF: 0.00853 AC: 1297 AN: 152098 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.0300

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00215 AC: 540 AN: 251488 Hom.: 6 AF XY: 0.00146 AC XY: 198 AN XY: 135918

Gnomad AFR exome AF: 0.0293

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000814

GnomAD4 exome AF: 0.000853 AC: 1246 AN: 1461010 Hom.: 15 Cov.: 30 AF XY: 0.000721 AC XY: 524 AN XY: 726760

Gnomad4 AFR exome AF: 0.0293

Gnomad4 AMR exome AF: 0.00165

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000324

Gnomad4 OTH exome AF: 0.00247

GnomAD4 genome AF: 0.00853 AC: 1298 AN: 152216 Hom.: 14 Cov.: 32 AF XY: 0.00811 AC XY: 604 AN XY: 74440

Gnomad4 AFR AF: 0.0300

Gnomad4 AMR AF: 0.00242

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00186 Hom.: 3

Bravo AF: 0.00967

ESP6500AA AF: 0.0340 AC: 150

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00278 AC: 338

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 16, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.018	T;T;T;.;T;T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D
MetaRNN	Benign	0.0089	T;T;T;T;T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.9	.;.;L;.;.;.
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.9	N;.;N;N;.;D
REVEL	Benign	0.20
Sift	Benign	0.27	T;.;T;T;.;D
Sift4G	Benign	0.34	T;T;T;T;T;T
Polyphen		0.98	D;.;D;.;.;.
Vest4		0.54
MVP		0.90
MPC		1.1
ClinPred		0.028	T
GERP RS		4.2
Varity_R		0.083
gMVP		0.75

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: rs35712717; hg19: chr7-45956197;