rs17013181

Variant names:

• chr4-87811611-A-G
• rs17013181
• NM_004967.4:c.655A>G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004967.4(IBSP):​c.655A>G​(p.Arg219Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.224 in 1,613,262 control chromosomes in the GnomAD database, including 41,893 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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: 𝑓 0.26 (5463 hom., cov: 30)
  • Exomes 𝑓: 0.22 (36430 hom.)
• Consequence: IBSP NM_004967.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.210

Genes affected

IBSP (HGNC:5341): (integrin binding sialoprotein) The protein encoded by this gene is a major structural protein of the bone matrix. It constitutes approximately 12% of the noncollagenous proteins in human bone and is synthesized by skeletal-associated cell types, including hypertrophic chondrocytes, osteoblasts, osteocytes, and osteoclasts. The only extraskeletal site of its synthesis is the trophoblast. This protein binds to calcium and hydroxyapatite via its acidic amino acid clusters, and mediates cell attachment through an RGD sequence that recognizes the vitronectin receptor. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003080666).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.371 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IBSP	NM_004967.4	c.655A>G	p.Arg219Gly	missense_variant	Exon 7 of 7	ENST00000226284.7	NP_004958.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IBSP	ENST00000226284.7	c.655A>G	p.Arg219Gly	missense_variant	Exon 7 of 7	1	NM_004967.4	ENSP00000226284.5

Frequencies

GnomAD3 genomes AF: 0.255 AC: 38702 AN: 151620 Hom.: 5455 Cov.: 30

Gnomad AFR AF: 0.376

Gnomad AMI AF: 0.277

Gnomad AMR AF: 0.255

Gnomad ASJ AF: 0.113

Gnomad EAS AF: 0.213

Gnomad SAS AF: 0.153

Gnomad FIN AF: 0.155

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.216

Gnomad OTH AF: 0.239

GnomAD3 exomes AF: 0.208 AC: 52174 AN: 250694 Hom.: 5849 AF XY: 0.202 AC XY: 27337 AN XY: 135470

Gnomad AFR exome AF: 0.386

Gnomad AMR exome AF: 0.224

Gnomad ASJ exome AF: 0.119

Gnomad EAS exome AF: 0.205

Gnomad SAS exome AF: 0.149

Gnomad FIN exome AF: 0.153

Gnomad NFE exome AF: 0.213

Gnomad OTH exome AF: 0.207

GnomAD4 exome AF: 0.220 AC: 322026 AN: 1461524 Hom.: 36430 Cov.: 53 AF XY: 0.217 AC XY: 157853 AN XY: 727060

Gnomad4 AFR exome AF: 0.377

Gnomad4 AMR exome AF: 0.230

Gnomad4 ASJ exome AF: 0.118

Gnomad4 EAS exome AF: 0.256

Gnomad4 SAS exome AF: 0.154

Gnomad4 FIN exome AF: 0.156

Gnomad4 NFE exome AF: 0.225

Gnomad4 OTH exome AF: 0.221

GnomAD4 genome AF: 0.255 AC: 38746 AN: 151738 Hom.: 5463 Cov.: 30 AF XY: 0.250 AC XY: 18505 AN XY: 74150

Gnomad4 AFR AF: 0.376

Gnomad4 AMR AF: 0.256

Gnomad4 ASJ AF: 0.113

Gnomad4 EAS AF: 0.213

Gnomad4 SAS AF: 0.152

Gnomad4 FIN AF: 0.155

Gnomad4 NFE AF: 0.216

Gnomad4 OTH AF: 0.237

Alfa AF: 0.220 Hom.: 8839

Bravo AF: 0.270

TwinsUK AF: 0.223 AC: 827

ALSPAC AF: 0.229 AC: 884

ESP6500AA AF: 0.361 AC: 1590

ESP6500EA AF: 0.220 AC: 1890

ExAC AF: 0.211 AC: 25572

Asia WGS AF: 0.227 AC: 792 AN: 3478

EpiCase AF: 0.213

EpiControl AF: 0.209

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.86	T
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.7
DANN	Benign	0.83
DEOGEN2	Benign	0.032	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0018	N
LIST_S2	Benign	0.25	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-0.29	N
PrimateAI	Benign	0.19	T
PROVEAN	Benign	0.33	N
REVEL	Benign	0.021
Sift	Benign	0.23	T
Sift4G	Benign	0.36	T
Polyphen		0.0	B
Vest4		0.010
MPC		0.18
ClinPred		0.0012	T
GERP RS		3.3
Varity_R		0.059
gMVP		0.32

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: rs17013181; hg19: chr4-88732763; COSMIC: COSV56897013;