NM_000599.4:c.467G>T

Variant names:

• chr2-216678950-C-A
• rs201801158
• NM_000599.4:c.467G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000599.4(IGFBP5):​c.467G>T​(p.Arg156Leu) 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. 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. R156H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IGFBP5 NM_000599.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.35
• Publications: 0 publications found

Genes affected

IGFBP5 (HGNC:5474): (insulin like growth factor binding protein 5) Enables insulin-like growth factor I binding activity. Involved in several processes, including cellular response to cAMP; regulation of smooth muscle cell migration; and regulation of smooth muscle cell proliferation. Part of insulin-like growth factor ternary complex. Biomarker of pulmonary fibrosis. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2680303).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGFBP5	NM_000599.4	c.467G>T	p.Arg156Leu	missense_variant	Exon 2 of 4	ENST00000233813.5	NP_000590.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGFBP5	ENST00000233813.5	c.467G>T	p.Arg156Leu	missense_variant	Exon 2 of 4	1	NM_000599.4	ENSP00000233813.4
IGFBP5	ENST00000449583.1	c.602G>T	p.Arg201Leu	missense_variant	Exon 2 of 2	3		ENSP00000413474.1
IGFBP5	ENST00000486341.1	n.359G>T		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Benign	-0.061	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D;.
Eigen	Benign	0.10
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.27	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L;.
PhyloP100		3.4
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.1	D;N
REVEL	Benign	0.075
Sift	Uncertain	0.013	D;D
Sift4G	Benign	0.12	T;T
Polyphen		0.65	P;.
Vest4		0.60
MutPred		0.39		Loss of methylation at K158 (P = 0.0268);.;
MVP		0.36
MPC		0.84
ClinPred		0.94	D
GERP RS		4.0
Varity_R		0.31
gMVP		0.55
Mutation Taster		=81/19	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: rs201801158; hg19: chr2-217543673;