chr4-87811540-G-A

Variant names:

• chr4-87811540-G-A
• rs1054627
• NM_004967.4:c.584G>A

Variant summary

Our verdict is Benign. The variant received -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. 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.

• 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
• Publications: 54 publications found

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]

ENSG00000307815 (HGNC:58843):

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004967.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IBSP	NM_004967.4	MANE Select	c.584G>A	p.Gly195Glu	missense	Exon 7 of 7	NP_004958.2	P21815

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IBSP	ENST00000226284.7	TSL:1 MANE Select	c.584G>A	p.Gly195Glu	missense	Exon 7 of 7	ENSP00000226284.5	P21815
	IBSP	ENST00000883247.1		c.584G>A	p.Gly195Glu	missense	Exon 7 of 7	ENSP00000553306.1
	ENSG00000307815	ENST00000829020.1		n.286-25092C>T		intron	N/A

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

GnomAD2 exomes AF: 0.298 AC: 74627 AN: 250650 AF XY: 0.305

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 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

African (AFR) AF: 0.0469 AC: 1570 AN: 33478

American (AMR) AF: 0.318 AC: 14226 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.461 AC: 12039 AN: 26128

East Asian (EAS) AF: 0.123 AC: 4887 AN: 39678

South Asian (SAS) AF: 0.327 AC: 28223 AN: 86248

European-Finnish (FIN) AF: 0.350 AC: 18691 AN: 53404

Middle Eastern (MID) AF: 0.232 AC: 1338 AN: 5768

European-Non Finnish (NFE) AF: 0.315 AC: 349751 AN: 1111834

Other (OTH) AF: 0.293 AC: 17698 AN: 60382

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

African (AFR) AF: 0.0606 AC: 2513 AN: 41478

American (AMR) AF: 0.285 AC: 4339 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.465 AC: 1612 AN: 3468

East Asian (EAS) AF: 0.120 AC: 617 AN: 5160

South Asian (SAS) AF: 0.326 AC: 1561 AN: 4788

European-Finnish (FIN) AF: 0.357 AC: 3765 AN: 10540

Middle Eastern (MID) AF: 0.236 AC: 69 AN: 292

European-Non Finnish (NFE) AF: 0.316 AC: 21484 AN: 67914

Other (OTH) AF: 0.249 AC: 524 AN: 2108

Alfa AF: 0.297 Hom.: 27228

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 v4.9

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
PhyloP100		1.5
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
Mutation Taster		=99/1	polymorphism (auto)

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