4-57110102-C-T

Variant names:

• chr4-57110102-C-T
• NM_001553.3:c.250G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001553.3(IGFBP7):​c.250G>A​(p.Gly84Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000217 in 1,382,286 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: IGFBP7 NM_001553.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.03

Genes affected

IGFBP7 (HGNC:5476): (insulin like growth factor binding protein 7) This gene encodes a member of the insulin-like growth factor (IGF)-binding protein (IGFBP) family. IGFBPs bind IGFs with high affinity, and regulate IGF availability in body fluids and tissues and modulate IGF binding to its receptors. This protein binds IGF-I and IGF-II with relatively low affinity, and belongs to a subfamily of low-affinity IGFBPs. It also stimulates prostacyclin production and cell adhesion. Alternatively spliced transcript variants encoding different isoforms have been described for this gene, and one variant has been associated with retinal arterial macroaneurysm (PMID:21835307). [provided by RefSeq, Dec 2011]

IGFBP7-AS1 (HGNC:40296): (IGFBP7 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGFBP7	NM_001553.3	c.250G>A	p.Gly84Ser	missense_variant	Exon 1 of 5	ENST00000295666.6	NP_001544.1
IGFBP7	NM_001253835.2	c.250G>A	p.Gly84Ser	missense_variant	Exon 1 of 4		NP_001240764.1
IGFBP7-AS1	NR_034081.1	n.209+132C>T		intron_variant	Intron 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGFBP7	ENST00000295666.6	c.250G>A	p.Gly84Ser	missense_variant	Exon 1 of 5	1	NM_001553.3	ENSP00000295666.4
IGFBP7-AS1	ENST00000499667.6	n.209+132C>T		intron_variant	Intron 1 of 4	1
IGFBP7	ENST00000514062.2	c.250G>A	p.Gly84Ser	missense_variant	Exon 1 of 4	2		ENSP00000486293.1
IGFBP7-AS1	ENST00000508328.6	n.191+132C>T		intron_variant	Intron 1 of 3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000217 AC: 3 AN: 1382286 Hom.: 0 Cov.: 30 AF XY: 0.00000439 AC XY: 3 AN XY: 683076

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000127

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000185

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jul 13, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.250G>A (p.G84S) alteration is located in exon 1 (coding exon 1) of the IGFBP7 gene. This alteration results from a G to A substitution at nucleotide position 250, causing the glycine (G) at amino acid position 84 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Uncertain	0.014	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T;.
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.83	T;T
M_CAP	Pathogenic	0.79	D
MetaRNN	Uncertain	0.49	T;T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Uncertain	2.6	M;M
PrimateAI	Pathogenic	0.94	D
PROVEAN	Uncertain	-2.6	D;.
REVEL	Uncertain	0.31
Sift	Uncertain	0.0060	D;.
Sift4G	Uncertain	0.013	D;D
Polyphen		0.94	P;.
Vest4		0.28
MutPred		0.32		Gain of sheet (P = 0.0125);Gain of sheet (P = 0.0125);
MVP		0.60
MPC		1.3
ClinPred		0.99	D
GERP RS		3.5
Varity_R		0.83
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-57976268;