4-87811824-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004967.4(IBSP):c.868T>C(p.Tyr290His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: IBSP NM_004967.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.88

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IBSP	NM_004967.4	c.868T>C	p.Tyr290His	missense_variant	7/7	ENST00000226284.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IBSP	ENST00000226284.7	c.868T>C	p.Tyr290His	missense_variant	7/7	1	NM_004967.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 07, 2023

The c.868T>C (p.Y290H) alteration is located in exon 7 (coding exon 6) of the IBSP gene. This alteration results from a T to C substitution at nucleotide position 868, causing the tyrosine (Y) at amino acid position 290 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Benign	-0.029	T
BayesDel_noAF	Benign	-0.28
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.38	T
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.9	M
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.27
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.18	T
Polyphen		1.0	D
Vest4		0.57
MutPred		0.70		Gain of glycosylation at Y290 (P = 0.0061);
MVP		0.46
MPC		0.70
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.53
gMVP		0.44

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-88732976;