rs1054627

Positions:

• chr4-87811540-G-A

Variant summary

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

The NM_004967.4(IBSP):​c.584G>A​(p.Gly195Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.301 in 1,613,492 control chromosomes in the GnomAD database, including 77,554 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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 same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.24 (5720 hom., cov: 30)
  • Exomes 𝑓: 0.31 (71834 hom.)
• Consequence: IBSP NM_004967.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.51

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=0.0042069852).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.313 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IBSP	NM_004967.4	c.584G>A	p.Gly195Glu	missense_variant	7/7	ENST00000226284.7	NP_004958.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IBSP	ENST00000226284.7	c.584G>A	p.Gly195Glu	missense_variant	7/7	1	NM_004967.4	ENSP00000226284.5

Frequencies

GnomAD3 genomes AF: 0.243 AC: 36923 AN: 151786 Hom.: 5721 Cov.: 30

Gnomad AFR AF: 0.0608

Gnomad AMI AF: 0.471

Gnomad AMR AF: 0.285

Gnomad ASJ AF: 0.465

Gnomad EAS AF: 0.120

Gnomad SAS AF: 0.326

Gnomad FIN AF: 0.357

Gnomad MID AF: 0.239

Gnomad NFE AF: 0.316

Gnomad OTH AF: 0.251

GnomAD3 exomes AF: 0.298 AC: 74627 AN: 250650 Hom.: 12128 AF XY: 0.305 AC XY: 41296 AN XY: 135454

Gnomad AFR exome AF: 0.0533

Gnomad AMR exome AF: 0.324

Gnomad ASJ exome AF: 0.455

Gnomad EAS exome AF: 0.122

Gnomad SAS exome AF: 0.329

Gnomad FIN exome AF: 0.355

Gnomad NFE exome AF: 0.319

Gnomad OTH exome AF: 0.315

GnomAD4 exome AF: 0.307 AC: 448423 AN: 1461588 Hom.: 71834 Cov.: 51 AF XY: 0.309 AC XY: 224495 AN XY: 727094

Gnomad4 AFR exome AF: 0.0469

Gnomad4 AMR exome AF: 0.318

Gnomad4 ASJ exome AF: 0.461

Gnomad4 EAS exome AF: 0.123

Gnomad4 SAS exome AF: 0.327

Gnomad4 FIN exome AF: 0.350

Gnomad4 NFE exome AF: 0.315

Gnomad4 OTH exome AF: 0.293

GnomAD4 genome AF: 0.243 AC: 36912 AN: 151904 Hom.: 5720 Cov.: 30 AF XY: 0.247 AC XY: 18359 AN XY: 74254

Gnomad4 AFR AF: 0.0606

Gnomad4 AMR AF: 0.285

Gnomad4 ASJ AF: 0.465

Gnomad4 EAS AF: 0.120

Gnomad4 SAS AF: 0.326

Gnomad4 FIN AF: 0.357

Gnomad4 NFE AF: 0.316

Gnomad4 OTH AF: 0.249

Alfa AF: 0.309 Hom.: 19539

Bravo AF: 0.230

TwinsUK AF: 0.315 AC: 1169

ALSPAC AF: 0.304 AC: 1171

ESP6500AA AF: 0.0651 AC: 287

ESP6500EA AF: 0.320 AC: 2756

ExAC AF: 0.293 AC: 35574

Asia WGS AF: 0.205 AC: 713 AN: 3478

EpiCase AF: 0.318

EpiControl AF: 0.318

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	19
DANN	Benign	0.92
DEOGEN2	Benign	0.037	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.37	T
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.6	M
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.086
Sift	Benign	0.58	T
Sift4G	Benign	0.78	T
Polyphen		0.23	B
Vest4		0.016
MPC		0.67
ClinPred		0.0093	T
GERP RS		2.2
Varity_R		0.072
gMVP		0.11

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: rs1054627; hg19: chr4-88732692; COSMIC: COSV56895435;