Genetic Variant NM_006475.3:c.1792G>C (chr13-37579121-C-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_006475.3(POSTN):c.1792G>C(p.Val598Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V598I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

POSTN
NM_006475.3 missense, splice_region

Scores

Splicing: ADA: 0.9685

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.57

Publications

0 publications found

Variant links:

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]

POSTN links:

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ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
POSTN	NM_006475.3	MANE Select	c.1792G>C	p.Val598Leu	missense splice_region	Exon 14 of 23	NP_006466.2	Q15063-1
POSTN	NM_001286665.2		c.1792G>C	p.Val598Leu	missense splice_region	Exon 14 of 22	NP_001273594.1	Q15063-5
POSTN	NM_001330517.2		c.1792G>C	p.Val598Leu	missense splice_region	Exon 14 of 22	NP_001317446.1	Q15063-8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
POSTN	ENST00000379747.9	TSL:1 MANE Select	c.1792G>C	p.Val598Leu	missense splice_region	Exon 14 of 23	ENSP00000369071.4	Q15063-1
POSTN	ENST00000379743.8	TSL:1	c.1792G>C	p.Val598Leu	missense splice_region	Exon 14 of 22	ENSP00000369067.4	Q15063-5
POSTN	ENST00000541179.5	TSL:1	c.1792G>C	p.Val598Leu	missense splice_region	Exon 14 of 21	ENSP00000437959.1	Q15063-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000402

AC:

AN:

248932

AF XY:

0.00000743

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000890

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Uncertain

0.073

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.24

Eigen

Benign

-0.0086

Eigen_PC

Benign

0.12

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.037

MetaRNN

Benign

0.31

MetaSVM

Uncertain

0.29

MutationAssessor

Benign

1.7

PhyloP100

3.6

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.0

REVEL

Uncertain

0.47

Sift

Benign

0.24

Sift4G

Benign

0.27

Polyphen

0.083

Vest4

0.34

MutPred

0.45

Gain of catalytic residue at V598 (P = 0.0379)

MVP

0.87

MPC

0.25

ClinPred

0.46

GERP RS

5.3

Varity_R

0.36

gMVP

0.66

Mutation Taster

=59/41

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.97

dbscSNV1_RF

Pathogenic

0.89

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over