NM_000598.5:c.700G>A

Variant names:

• chr7-45916598-C-T
• rs35712717
• NM_000598.5:c.700G>A

Variant summary

Our verdict is Benign. The variant received -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 variant affecting the same amino acid position, but resulting in a different missense (i.e. G234D) has been classified as Uncertain significance.

• 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
• Publications: 5 publications found

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

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000598.5. 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
	IGFBP3	NM_000598.5	MANE Select	c.700G>A	p.Gly234Ser	missense	Exon 3 of 5	NP_000589.2	P17936-1
	IGFBP3	NM_001013398.2		c.718G>A	p.Gly240Ser	missense	Exon 3 of 5	NP_001013416.1	P17936-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGFBP3	ENST00000613132.5	TSL:5 MANE Select	c.700G>A	p.Gly234Ser	missense	Exon 3 of 5	ENSP00000477772.2	P17936-1
	IGFBP3	ENST00000908406.1		c.790G>A	p.Gly264Ser	missense	Exon 4 of 6	ENSP00000578465.1
	IGFBP3	ENST00000381083.9	TSL:5	c.718G>A	p.Gly240Ser	missense	Exon 3 of 5	ENSP00000370473.4	P17936-2

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

GnomAD2 exomes AF: 0.00215 AC: 540 AN: 251488 AF XY: 0.00146

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 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

African (AFR) AF: 0.0293 AC: 981 AN: 33464

American (AMR) AF: 0.00165 AC: 74 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5762

European-Non Finnish (NFE) AF: 0.0000324 AC: 36 AN: 1111284

Other (OTH) AF: 0.00247 AC: 149 AN: 60352

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

African (AFR) AF: 0.0300 AC: 1244 AN: 41508

American (AMR) AF: 0.00242 AC: 37 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68020

Other (OTH) AF: 0.00568 AC: 12 AN: 2112

Alfa AF: 0.00349 Hom.: 15

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0089	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.9	L
PhyloP100		4.6
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.20
Sift	Benign	0.27	T
Sift4G	Benign	0.34	T
Polyphen		0.98	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
Mutation Taster		=86/14	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: rs35712717; hg19: chr7-45956197;