9-98986035-T-C

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.571T>C(p.Ser191Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000849 in 1,614,096 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0046 (7 hom., cov: 33)
  • Exomes 𝑓: 0.00045 (6 hom.)
• Consequence: COL15A1 NM_001855.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.334

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=0.004239887).
• BP6: Variant 9-98986035-T-C is Benign according to our data. Variant chr9-98986035-T-C is described in ClinVar as [Benign]. Clinvar id is 3043699.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00464 (706/152272) while in subpopulation AFR AF= 0.0162 (672/41552). AF 95% confidence interval is 0.0152. There are 7 homozygotes in gnomad4. There are 333 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL15A1	NM_001855.5	c.571T>C	p.Ser191Pro	missense_variant	3/42	ENST00000375001.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL15A1	ENST00000375001.8	c.571T>C	p.Ser191Pro	missense_variant	3/42	1	NM_001855.5	P1
COL15A1	ENST00000471477.1	n.994T>C		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes AF: 0.00457 AC: 695 AN: 152154 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.0159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.00120 AC: 300 AN: 250760 Hom.: 2 AF XY: 0.000892 AC XY: 121 AN XY: 135686

Gnomad AFR exome AF: 0.0165

Gnomad AMR exome AF: 0.000839

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000455 AC: 665 AN: 1461824 Hom.: 6 Cov.: 34 AF XY: 0.000397 AC XY: 289 AN XY: 727214

Gnomad4 AFR exome AF: 0.0167

Gnomad4 AMR exome AF: 0.00103

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.000844

GnomAD4 genome AF: 0.00464 AC: 706 AN: 152272 Hom.: 7 Cov.: 33 AF XY: 0.00447 AC XY: 333 AN XY: 74462

Gnomad4 AFR AF: 0.0162

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000679 Hom.: 1

Bravo AF: 0.00510

ESP6500AA AF: 0.0143 AC: 63

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00154 AC: 187

Asia WGS AF: 0.00433 AC: 15 AN: 3478

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

Jun 07, 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	0.069
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.13
Dann	Benign	0.34
DEOGEN2	Benign	0.064	T;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.53	T;T
MetaRNN	Benign	0.0042	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-0.27	N;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.71	N;.
REVEL	Benign	0.010
Sift	Benign	0.45	T;.
Sift4G	Benign	1.0	T;T
Polyphen		0.081	B;.
Vest4		0.070
MVP		0.22
MPC		0.091
ClinPred		0.014	T
GERP RS		-3.5
Varity_R		0.052
gMVP		0.41

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: rs113791685; hg19: chr9-101748317;