4-57110120-T-C

Position:

• chr4-57110120-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.232A>G​(p.Arg78Gly) 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 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 the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: IGFBP7 NM_001553.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.422

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=0.05428633).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGFBP7	NM_001553.3	c.232A>G	p.Arg78Gly	missense_variant	1/5	ENST00000295666.6	NP_001544.1
IGFBP7	NM_001253835.2	c.232A>G	p.Arg78Gly	missense_variant	1/4		NP_001240764.1
IGFBP7-AS1	NR_034081.1	n.209+150T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGFBP7	ENST00000295666.6	c.232A>G	p.Arg78Gly	missense_variant	1/5	1	NM_001553.3	ENSP00000295666.4
IGFBP7-AS1	ENST00000499667.6	n.209+150T>C		intron_variant		1
IGFBP7	ENST00000514062.2	c.232A>G	p.Arg78Gly	missense_variant	1/4	2		ENSP00000486293.1
IGFBP7-AS1	ENST00000508328.6	n.191+150T>C		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1360504 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 671432

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000111 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	19
DANN	Benign	0.77
DEOGEN2	Benign	0.018	T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.44	T;T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.054	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.1	N;N
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-1.4	N;.
REVEL	Benign	0.034
Sift	Benign	0.29	T;.
Sift4G	Benign	0.44	T;T
Polyphen		0.012	B;.
Vest4		0.25
MutPred		0.30		Loss of methylation at R78 (P = 0.0126);Loss of methylation at R78 (P = 0.0126);
MVP		0.067
MPC		0.55
ClinPred		0.18	T
GERP RS		0.94
Varity_R		0.18
gMVP		0.46

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: rs11555284; hg19: chr4-57976286; COSMIC: COSV55271255;