rs140447227

Variant names:

• chr4-87811421-G-C
• rs140447227
• NM_004967.4:c.465G>C

Your query was ambiguous. Multiple possible variants found:

• chr4-87811421-G-C
• chr4-87811421-G-A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_004967.4(IBSP):​c.465G>C​(p.Glu155Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000138 in 1,613,264 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00020 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: IBSP NM_004967.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.35
• Publications: 0 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010193408).
• BS2: High AC in GnomAd4 at 30 AD gene.

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.465G>C	p.Glu155Asp	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.465G>C	p.Glu155Asp	missense	Exon 7 of 7	ENSP00000226284.5	P21815
	IBSP	ENST00000883247.1		c.465G>C	p.Glu155Asp	missense	Exon 7 of 7	ENSP00000553306.1
	ENSG00000307815	ENST00000829020.1		n.286-24973C>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152062 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000180 AC: 45 AN: 249926 AF XY: 0.000215

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000302

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000131 AC: 192 AN: 1461084 Hom.: 0 Cov.: 38 AF XY: 0.000133 AC XY: 97 AN XY: 726848

African (AFR) AF: 0.0000598 AC: 2 AN: 33444

American (AMR) AF: 0.0000224 AC: 1 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39626

South Asian (SAS) AF: 0.000255 AC: 22 AN: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5762

European-Non Finnish (NFE) AF: 0.000139 AC: 154 AN: 1111454

Other (OTH) AF: 0.000166 AC: 10 AN: 60366

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152180 Hom.: 1 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74400

African (AFR) AF: 0.0000723 AC: 3 AN: 41518

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 67994

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000201 Hom.: 0

Bravo AF: 0.000215

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.000231 AC: 28

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000416

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	3.5
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.86
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.079	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		-1.3
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.11
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.050	T
Polyphen		0.63	P
Vest4		0.14
MutPred		0.51		Loss of loop (P = 0.2237)
MVP		0.27
MPC		0.56
ClinPred		0.060	T
GERP RS		-1.7
Varity_R		0.30
gMVP		0.064
Mutation Taster		=77/23	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: rs140447227; hg19: chr4-88732573;