9-98985603-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001855.5(COL15A1):c.139A>G(p.Ile47Val) variant causes a missense change. The variant allele was found at a frequency of 0.00254 in 1,614,180 control chromosomes in the GnomAD database, including 98 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.013 (50 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (48 hom.)
• Consequence: COL15A1 NM_001855.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.76

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005355954).
• BP6: Variant 9-98985603-A-G is Benign according to our data. Variant chr9-98985603-A-G is described in ClinVar as [Benign]. Clinvar id is 3056690.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0134 (2043/152352) while in subpopulation AFR AF= 0.047 (1952/41570). AF 95% confidence interval is 0.0452. There are 50 homozygotes in gnomad4. There are 950 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 50 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL15A1	NM_001855.5	c.139A>G	p.Ile47Val	missense_variant	3/42	ENST00000375001.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL15A1	ENST00000375001.8	c.139A>G	p.Ile47Val	missense_variant	3/42	1	NM_001855.5	P1
COL15A1	ENST00000471477.1	n.562A>G		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes AF: 0.0134 AC: 2037 AN: 152234 Hom.: 50 Cov.: 33

Gnomad AFR AF: 0.0469

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00412

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00764

GnomAD3 exomes AF: 0.00355 AC: 891 AN: 251074 Hom.: 19 AF XY: 0.00254 AC XY: 344 AN XY: 135696

Gnomad AFR exome AF: 0.0490

Gnomad AMR exome AF: 0.00194

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00140 AC: 2052 AN: 1461828 Hom.: 48 Cov.: 31 AF XY: 0.00126 AC XY: 917 AN XY: 727200

Gnomad4 AFR exome AF: 0.0496

Gnomad4 AMR exome AF: 0.00219

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000737

Gnomad4 OTH exome AF: 0.00295

GnomAD4 genome AF: 0.0134 AC: 2043 AN: 152352 Hom.: 50 Cov.: 33 AF XY: 0.0128 AC XY: 950 AN XY: 74506

Gnomad4 AFR AF: 0.0470

Gnomad4 AMR AF: 0.00411

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00756

Alfa AF: 0.00301 Hom.: 22

Bravo AF: 0.0155

ESP6500AA AF: 0.0474 AC: 209

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00460 AC: 559

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

COL15A1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 12, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.76
Cadd	Benign	15
Dann	Benign	0.93
DEOGEN2	Benign	0.050	T;T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.63	T;T
MetaRNN	Benign	0.0054	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.0	L;.
MutationTaster	Benign	0.95	N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.59	N;.
REVEL	Benign	0.067
Sift	Benign	0.20	T;.
Sift4G	Benign	0.10	T;T
Polyphen		0.15	B;.
Vest4		0.10
MVP		0.44
MPC		0.23
ClinPred		0.031	T
GERP RS		1.5
Varity_R		0.033
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs115245175; hg19: chr9-101747885;