chr7-45921046-G-C

Position:

• chr7-45921046-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000598.5(IGFBP3):​c.95C>G​(p.Ala32Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.399 in 1,441,040 control chromosomes in the GnomAD database, including 118,622 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.38 (11466 hom., cov: 33)
  • Exomes 𝑓: 0.40 (107156 hom.)
• Consequence: IGFBP3 NM_000598.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.359

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.1002727E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.732 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGFBP3	NM_000598.5	c.95C>G	p.Ala32Gly	missense_variant	1/5	ENST00000613132.5	NP_000589.2
IGFBP3	NM_001013398.2	c.95C>G	p.Ala32Gly	missense_variant	1/5		NP_001013416.1
IGFBP3	XM_047420325.1	c.95C>G	p.Ala32Gly	missense_variant	1/4		XP_047276281.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGFBP3	ENST00000613132.5	c.95C>G	p.Ala32Gly	missense_variant	1/5	5	NM_000598.5	ENSP00000477772.2
IGFBP3	ENST00000381083.9	c.95C>G	p.Ala32Gly	missense_variant	1/5	5		ENSP00000370473.4
IGFBP3	ENST00000381086.9	c.9+86C>G		intron_variant		2		ENSP00000370476.4
IGFBP3	ENST00000448817.1	c.73+581C>G		intron_variant		4		ENSP00000389668.1

Frequencies

GnomAD3 genomes AF: 0.379 AC: 57281 AN: 151182 Hom.: 11477 Cov.: 33

Gnomad AFR AF: 0.312

Gnomad AMI AF: 0.584

Gnomad AMR AF: 0.321

Gnomad ASJ AF: 0.460

Gnomad EAS AF: 0.751

Gnomad SAS AF: 0.362

Gnomad FIN AF: 0.350

Gnomad MID AF: 0.474

Gnomad NFE AF: 0.403

Gnomad OTH AF: 0.386

GnomAD3 exomes AF: 0.382 AC: 21599 AN: 56480 Hom.: 4633 AF XY: 0.389 AC XY: 12740 AN XY: 32772

Gnomad AFR exome AF: 0.310

Gnomad AMR exome AF: 0.234

Gnomad ASJ exome AF: 0.485

Gnomad EAS exome AF: 0.782

Gnomad SAS exome AF: 0.351

Gnomad FIN exome AF: 0.381

Gnomad NFE exome AF: 0.421

Gnomad OTH exome AF: 0.421

GnomAD4 exome AF: 0.402 AC: 518243 AN: 1289750 Hom.: 107156 Cov.: 43 AF XY: 0.400 AC XY: 254181 AN XY: 634912

Gnomad4 AFR exome AF: 0.312

Gnomad4 AMR exome AF: 0.263

Gnomad4 ASJ exome AF: 0.475

Gnomad4 EAS exome AF: 0.761

Gnomad4 SAS exome AF: 0.345

Gnomad4 FIN exome AF: 0.349

Gnomad4 NFE exome AF: 0.401

Gnomad4 OTH exome AF: 0.408

GnomAD4 genome AF: 0.379 AC: 57274 AN: 151290 Hom.: 11466 Cov.: 33 AF XY: 0.377 AC XY: 27912 AN XY: 73960

Gnomad4 AFR AF: 0.311

Gnomad4 AMR AF: 0.320

Gnomad4 ASJ AF: 0.460

Gnomad4 EAS AF: 0.751

Gnomad4 SAS AF: 0.361

Gnomad4 FIN AF: 0.350

Gnomad4 NFE AF: 0.403

Gnomad4 OTH AF: 0.383

Alfa AF: 0.211 Hom.: 419

Bravo AF: 0.377

ExAC AF: 0.283 AC: 3944

Asia WGS AF: 0.484 AC: 1665 AN: 3440

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	7.9
DANN	Benign	0.95
DEOGEN2	Benign	0.27	T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.065	N
LIST_S2	Benign	0.47	T;T
MetaRNN	Benign	0.0000041	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.81	L;L
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.040	N;N
REVEL	Benign	0.017
Sift	Benign	0.38	T;T
Sift4G	Benign	0.91	T;T
Polyphen		0.0060	B;.
Vest4		0.059
MPC		0.54
ClinPred		0.0019	T
GERP RS		0.63
Varity_R		0.036
gMVP		0.43

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: rs2854746; hg19: chr7-45960645; COSMIC: COSV51872757; COSMIC: COSV51872757;