7-45916597-C-A

Variant names:

• chr7-45916597-C-A
• rs185515234
• NM_000598.5:c.701G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000598.5(IGFBP3):​c.701G>T​(p.Gly234Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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: not found (cov: 32)
• Consequence: IGFBP3 NM_000598.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.01
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.752

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.701G>T	p.Gly234Val	missense	Exon 3 of 5	NP_000589.2	P17936-1
	IGFBP3	NM_001013398.2		c.719G>T	p.Gly240Val	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.701G>T	p.Gly234Val	missense	Exon 3 of 5	ENSP00000477772.2	P17936-1
	IGFBP3	ENST00000908406.1		c.791G>T	p.Gly264Val	missense	Exon 4 of 6	ENSP00000578465.1
	IGFBP3	ENST00000381083.9	TSL:5	c.719G>T	p.Gly240Val	missense	Exon 3 of 5	ENSP00000370473.4	P17936-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Benign	0.15
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.043	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Benign	-0.37	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		3.0
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-4.4	D
REVEL	Uncertain	0.47
Sift	Benign	0.072	T
Sift4G	Benign	0.077	T
Polyphen		0.95	P
Vest4		0.76
MutPred		0.63		Loss of disorder (P = 0.0649)
MVP		0.89
MPC		1.2
ClinPred		0.98	D
GERP RS		4.2
Varity_R		0.39
gMVP		0.86
Mutation Taster		=58/42	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: rs185515234; hg19: chr7-45956196;