4-57110185-G-T

Variant names:

• chr4-57110185-G-T
• rs942974010
• NM_001553.3:c.167C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001553.3(IGFBP7):​c.167C>A​(p.Ala56Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000575 in 1,390,368 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. A56G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: IGFBP7 NM_001553.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0640
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08680609).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001553.3. 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
	IGFBP7	NM_001553.3	MANE Select	c.167C>A	p.Ala56Glu	missense	Exon 1 of 5	NP_001544.1	Q16270-1
	IGFBP7	NM_001253835.2		c.167C>A	p.Ala56Glu	missense	Exon 1 of 4	NP_001240764.1	Q16270-2
	IGFBP7-AS1	NR_034081.1		n.209+215G>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGFBP7	ENST00000295666.6	TSL:1 MANE Select	c.167C>A	p.Ala56Glu	missense	Exon 1 of 5	ENSP00000295666.4	Q16270-1
	IGFBP7-AS1	ENST00000499667.6	TSL:1	n.209+215G>T		intron	N/A
	IGFBP7	ENST00000896424.1		c.167C>A	p.Ala56Glu	missense	Exon 1 of 7	ENSP00000566483.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151844 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.00 AC: 0 AN: 17366 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000484 AC: 6 AN: 1238524 Hom.: 0 Cov.: 30 AF XY: 0.00000330 AC XY: 2 AN XY: 605204

African (AFR) AF: 0.00 AC: 0 AN: 24610

American (AMR) AF: 0.00 AC: 0 AN: 13116

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17872

East Asian (EAS) AF: 0.0000362 AC: 1 AN: 27658

South Asian (SAS) AF: 0.00 AC: 0 AN: 56128

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30458

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3712

European-Non Finnish (NFE) AF: 9.86e-7 AC: 1 AN: 1013850

Other (OTH) AF: 0.0000782 AC: 4 AN: 51120

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151844 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74172

African (AFR) AF: 0.00 AC: 0 AN: 41388

American (AMR) AF: 0.00 AC: 0 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10496

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67922

Other (OTH) AF: 0.000480 AC: 1 AN: 2084

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.0045	T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.62	T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.087	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.064
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	0.52	N
REVEL	Benign	0.15
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.98	D
Vest4		0.20
MutPred		0.19		Gain of glycosylation at T53 (P = 0.0969)
MVP		0.16
MPC		1.0
ClinPred		0.49	T
GERP RS		3.5
PromoterAI		0.076	Neutral
Varity_R		0.17
gMVP		0.61
Mutation Taster		=88/12	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: rs942974010; hg19: chr4-57976351;