Genetic Variant COL15A1:p.Thr391Arg (chr9-99003559-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001855.5(COL15A1):c.1172C>G(p.Thr391Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000714 in 1,399,860 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. 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. T391M) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

COL15A1
NM_001855.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.571

Variant links:

Genes affected

COL15A1 (HGNC:2192): (collagen type XV alpha 1 chain) This gene encodes the alpha chain of type XV collagen, a member of the FACIT collagen family (fibril-associated collagens with interrupted helices). Type XV collagen has a wide tissue distribution but the strongest expression is localized to basement membrane zones so it may function to adhere basement membranes to underlying connective tissue stroma. The proteolytically produced C-terminal fragment of type XV collagen is restin, a potentially antiangiogenic protein that is closely related to endostatin. Mouse studies have shown that collagen XV deficiency is associated with muscle and microvessel deterioration. [provided by RefSeq, May 2013]

COL15A1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.17255771).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL15A1	NM_001855.5 link	c.1172C>G	p.Thr391Arg	missense_variant	Exon 8 of 42	ENST00000375001.8	NP_001846.3	P39059B3KTP7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL15A1	ENST00000375001.8 link	c.1172C>G	p.Thr391Arg	missense_variant	Exon 8 of 42	1	NM_001855.5	ENSP00000364140.3		P39059

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.14e-7

AC:

AN:

1399860

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

694870

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30732

American (AMR)

AF:

0.00

AC:

AN:

36088

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24248

East Asian (EAS)

AF:

0.00

AC:

AN:

35660

South Asian (SAS)

AF:

0.00

AC:

AN:

77398

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52252

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5556

European-Non Finnish (NFE)

AF:

9.26e-7

AC:

AN:

1080438

Other (OTH)

AF:

0.00

AC:

AN:

57488

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Uncertain

0.029

BayesDel_noAF

Benign

-0.20

CADD

Benign

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.039

T;T

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.036

LIST_S2

Benign

0.71

T;T

M_CAP

Benign

0.079

MetaRNN

Benign

0.17

T;T

MetaSVM

Benign

-0.42

MutationAssessor

Benign

1.9

L;.

PhyloP100

0.57

PrimateAI

Benign

0.35

PROVEAN

Benign

-2.0

N;.

REVEL

Uncertain

0.29

Sift

Uncertain

0.0020

D;.

Sift4G

Benign

0.57

T;T

Polyphen

0.87

P;.

Vest4

0.34

MutPred

0.23

Loss of glycosylation at T391 (P = 0.0012);.;

MVP

0.69

MPC

0.27

ClinPred

0.30

GERP RS

1.9

Varity_R

0.10

gMVP

0.30

Mutation Taster

=96/4

polymorphism

(source)

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

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9-99003559-C-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

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