Genetic Variant IBSP:p.His48Tyr (chr4-87802690-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_004967.4(IBSP):c.142C>T(p.His48Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000295 in 1,566,324 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely benign (★).

Frequency

Genomes: 𝑓 0.0017 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

IBSP
NM_004967.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.03

Publications

0 publications found

Variant links:

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]

IBSP links:

ENSG00000307815 (HGNC:58843):

ENSG00000307815 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011366993).

BP6

Variant 4-87802690-C-T is Benign according to our data. Variant chr4-87802690-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 733884.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 256 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.142C>T	p.His48Tyr	missense	Exon 4 of 7	NP_004958.2	P21815

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IBSP	ENST00000226284.7	TSL:1 MANE Select	c.142C>T	p.His48Tyr	missense	Exon 4 of 7	ENSP00000226284.5	P21815
IBSP	ENST00000883247.1		c.142C>T	p.His48Tyr	missense	Exon 4 of 7	ENSP00000553306.1
ENSG00000307815	ENST00000829020.1		n.286-16242G>A		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00169

AC:

257

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00556

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00170

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000429

AC:

AN:

212316

AF XY:

0.000371

show subpopulations

Gnomad AFR exome

AF:

0.00541

Gnomad AMR exome

AF:

0.000413

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000146

AC:

206

AN:

1414108

Hom.:

Cov.:

AF XY:

0.000141

AC XY:

AN XY:

702628

show subpopulations

African (AFR)

AF:

0.00499

AC:

154

AN:

30870

American (AMR)

AF:

0.000579

AC:

AN:

31082

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24042

East Asian (EAS)

AF:

0.0000258

AC:

AN:

38788

South Asian (SAS)

AF:

0.0000130

AC:

AN:

76652

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52328

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4374

European-Non Finnish (NFE)

AF:

0.0000146

AC:

AN:

1097958

Other (OTH)

AF:

0.000276

AC:

AN:

58014

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.437

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00168

AC:

256

AN:

152216

Hom.:

Cov.:

AF XY:

0.00155

AC XY:

115

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.00551

AC:

229

AN:

41524

American (AMR)

AF:

0.00170

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68024

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000669

Hom.:

Bravo

AF:

0.00207

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00431

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000561

AC:

Asia WGS

AF:

0.000290

AC:

AN:

3464

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.042

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.35

LIST_S2

Benign

0.65

M_CAP

Benign

0.0031

MetaRNN

Benign

0.011

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.7

PhyloP100

1.0

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.39

REVEL

Benign

0.091

Sift

Benign

0.22

Sift4G

Benign

0.99

Polyphen

0.0060

Vest4

0.42

MVP

0.067

MPC

0.18

ClinPred

0.022

GERP RS

1.3

Varity_R

0.056

gMVP

0.57

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over