chr4-87810640-C-T

Variant names:

• chr4-87810640-C-T
• rs747891903
• NM_004967.4:c.281C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM1 BP4_Moderate BS2

The NM_004967.4(IBSP):​c.281C>T​(p.Ser94Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,460,968 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: IBSP NM_004967.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.95
• 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: Likely_benign. The variant received -4 ACMG points.

• PM1: In a modified_residue Phosphoserine (size 0) in uniprot entity SIAL_HUMAN
• BP4: Computational evidence support a benign effect (MetaRNN=0.14911756).
• BS2: High AC in GnomAdExome4 at 10 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.281C>T	p.Ser94Leu	missense	Exon 6 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.281C>T	p.Ser94Leu	missense	Exon 6 of 7	ENSP00000226284.5	P21815
	IBSP	ENST00000883247.1		c.281C>T	p.Ser94Leu	missense	Exon 6 of 7	ENSP00000553306.1
	ENSG00000307815	ENST00000829020.1		n.286-24192G>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1460968 Hom.: 0 Cov.: 29 AF XY: 0.00000826 AC XY: 6 AN XY: 726820

African (AFR) AF: 0.0000299 AC: 1 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111210

Other (OTH) AF: 0.00 AC: 0 AN: 60368

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

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	0.19
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.074	T
Eigen	Benign	-0.038
Eigen_PC	Benign	0.034
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PhyloP100		2.9
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.078
Sift	Benign	0.12	T
Sift4G	Benign	0.25	T
Polyphen		0.62	P
Vest4		0.30
MutPred		0.47		Gain of glycosylation at S94 (P = 0.0031)
MVP		0.47
MPC		0.21
ClinPred		0.73	D
GERP RS		4.4
Varity_R		0.14
gMVP		0.12
Mutation Taster		=86/14	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: rs747891903; hg19: chr4-88731792; COSMIC: COSV99883740;