rs3205088

Variant names:

• chr13-37586166-T-A
• rs3205088
• NM_006475.3:c.868A>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_006475.3(POSTN):​c.868A>T​(p.Ile290Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,728 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: POSTN NM_006475.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.55
• Publications: 0 publications found

Genes affected

POSTN (HGNC:16953): (periostin) This gene encodes a secreted extracellular matrix protein that functions in tissue development and regeneration, including wound healing, and ventricular remodeling following myocardial infarction. The encoded protein binds to integrins to support adhesion and migration of epithelial cells. This protein plays a role in cancer stem cell maintenance and metastasis. Mice lacking this gene exhibit cardiac valve disease, and skeletal and dental defects. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Sep 2015]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.815

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006475.3. 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
	POSTN	NM_006475.3	MANE Select	c.868A>T	p.Ile290Phe	missense	Exon 7 of 23	NP_006466.2
	POSTN	NM_001286665.2		c.868A>T	p.Ile290Phe	missense	Exon 7 of 22	NP_001273594.1
	POSTN	NM_001330517.2		c.868A>T	p.Ile290Phe	missense	Exon 7 of 22	NP_001317446.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POSTN	ENST00000379747.9	TSL:1 MANE Select	c.868A>T	p.Ile290Phe	missense	Exon 7 of 23	ENSP00000369071.4
	POSTN	ENST00000379743.8	TSL:1	c.868A>T	p.Ile290Phe	missense	Exon 7 of 22	ENSP00000369067.4
	POSTN	ENST00000541179.5	TSL:1	c.868A>T	p.Ile290Phe	missense	Exon 7 of 21	ENSP00000437959.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460728 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726694

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26090

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86086

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111270

Other (OTH) AF: 0.0000166 AC: 1 AN: 60332

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.43	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.069	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		3.6
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.053	T
Polyphen		1.0	D
Vest4		0.80
MutPred		0.72		Loss of stability (P = 0.0559)
MVP		0.84
MPC		0.29
ClinPred		0.89	D
GERP RS		5.8
Varity_R		0.78
gMVP		0.86
Mutation Taster		=42/58	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs3205088; hg19: chr13-38160303;