rs1133243

Positions:

• chr4-57110068-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001553.3(IGFBP7):​c.284A>G​(p.Lys95Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000256 in 1,559,944 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: IGFBP7 NM_001553.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.61

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06398392).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IGFBP7	NM_001553.3	c.284A>G	p.Lys95Arg	missense_variant	1/5	ENST00000295666.6
IGFBP7-AS1	NR_034081.1	n.209+98T>C		intron_variant, non_coding_transcript_variant
IGFBP7	NM_001253835.2	c.284A>G	p.Lys95Arg	missense_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGFBP7	ENST00000295666.6	c.284A>G	p.Lys95Arg	missense_variant	1/5	1	NM_001553.3	P2
IGFBP7-AS1	ENST00000499667.6	n.209+98T>C		intron_variant, non_coding_transcript_variant		1
IGFBP7-AS1	ENST00000508328.6	n.191+98T>C		intron_variant, non_coding_transcript_variant		3
IGFBP7	ENST00000514062.2	c.284A>G	p.Lys95Arg	missense_variant	1/4	2		A2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152074 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: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000213 AC: 3 AN: 1407870 Hom.: 0 Cov.: 31 AF XY: 0.00000143 AC XY: 1 AN XY: 697356

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000275

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152074 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74292

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000340

ExAC AF: 0.0000261 AC: 3

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	21
DANN	Benign	0.76
DEOGEN2	Benign	0.0037	T;.
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.60	T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.064	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.93	N;N
MutationTaster	Benign	0.88	D;D
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	-0.26	N;.
REVEL	Benign	0.021
Sift	Benign	0.49	T;.
Sift4G	Benign	0.28	T;T
Polyphen		0.0050	B;.
Vest4		0.20
MutPred		0.24		Loss of glycosylation at K95 (P = 0.0379);Loss of glycosylation at K95 (P = 0.0379);
MVP		0.40
MPC		0.35
ClinPred		0.074	T
GERP RS		2.0
Varity_R		0.061
gMVP		0.33

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: rs1133243; hg19: chr4-57976234;