4-57032532-T-G

Position:

• chr4-57032532-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The ENST00000295666.6(IGFBP7):​c.723A>C​(p.Glu241Asp) 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. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: IGFBP7 ENST00000295666.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.19

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]

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=0.079818696).
• BP6: Variant 4-57032532-T-G is Benign according to our data. Variant chr4-57032532-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 2479626.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGFBP7	NM_001553.3	c.723A>C	p.Glu241Asp	missense_variant	4/5	ENST00000295666.6	NP_001544.1
IGFBP7	NM_001253835.2	c.723A>C	p.Glu241Asp	missense_variant	4/4		NP_001240764.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGFBP7	ENST00000295666.6	c.723A>C	p.Glu241Asp	missense_variant	4/5	1	NM_001553.3	ENSP00000295666	P2
IGFBP7	ENST00000514062.2	c.723A>C	p.Glu241Asp	missense_variant	4/4	2		ENSP00000486293	A2
IGFBP7	ENST00000512512.3	n.363A>C		non_coding_transcript_exon_variant	4/5	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	7.8
DANN	Uncertain	0.99
DEOGEN2	Benign	0.020	T;.
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.64	T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.080	T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	0.95	N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.5	N;.
REVEL	Benign	0.072
Sift	Benign	0.11	T;.
Sift4G	Benign	0.10	T;T
Polyphen		0.54	P;.
Vest4		0.085
MutPred		0.39		Gain of glycosylation at Y246 (P = 0.0019);Gain of glycosylation at Y246 (P = 0.0019);
MVP		0.44
MPC		0.47
ClinPred		0.36	T
GERP RS		-2.5
Varity_R		0.089
gMVP		0.38

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-57898698;