chr19-9977595-C-G

Position:

• chr19-9977595-C-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_015719.4(COL5A3):​c.3125G>C​(p.Arg1042Pro) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.399 in 1,580,152 control chromosomes in the GnomAD database, including 126,938 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in Lovd as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.37 (10832 hom., cov: 32)
  • Exomes 𝑓: 0.40 (116106 hom.)
• Consequence: COL5A3 NM_015719.4 missense, splice_region
• Scores: Splicing: ADA: 0.00007224
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.92

Genes affected

COL5A3 (HGNC:14864): (collagen type V alpha 3 chain) This gene encodes an alpha chain for one of the low abundance fibrillar collagens. Fibrillar collagen molecules are trimers that can be composed of one or more types of alpha chains. Type V collagen is found in tissues containing type I collagen and appears to regulate the assembly of heterotypic fibers composed of both type I and type V collagen. This gene product is closely related to type XI collagen and it is possible that the collagen chains of types V and XI constitute a single collagen type with tissue-specific chain combinations. Mutations in this gene are thought to be responsible for the symptoms of a subset of patients with Ehlers-Danlos syndrome type III. Messages of several sizes can be detected in northern blots but sequence information cannot confirm the identity of the shorter messages. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.021603942).
• BP6: Variant 19-9977595-C-G is Benign according to our data. Variant chr19-9977595-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.404 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL5A3	NM_015719.4	c.3125G>C	p.Arg1042Pro	missense_variant, splice_region_variant	42/67	ENST00000264828.4	NP_056534.2
COL5A3	XM_011528042.3	c.3122G>C	p.Arg1041Pro	missense_variant, splice_region_variant	42/67		XP_011526344.1
COL5A3	XM_017026849.2	c.788G>C	p.Arg263Pro	missense_variant, splice_region_variant	15/40		XP_016882338.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL5A3	ENST00000264828.4	c.3125G>C	p.Arg1042Pro	missense_variant, splice_region_variant	42/67	1	NM_015719.4	ENSP00000264828.3

Frequencies

GnomAD3 genomes AF: 0.373 AC: 56728 AN: 151970 Hom.: 10820 Cov.: 32

Gnomad AFR AF: 0.351

Gnomad AMI AF: 0.508

Gnomad AMR AF: 0.291

Gnomad ASJ AF: 0.404

Gnomad EAS AF: 0.332

Gnomad SAS AF: 0.405

Gnomad FIN AF: 0.344

Gnomad MID AF: 0.396

Gnomad NFE AF: 0.408

Gnomad OTH AF: 0.343

GnomAD3 exomes AF: 0.368 AC: 82232 AN: 223238 Hom.: 15559 AF XY: 0.377 AC XY: 45277 AN XY: 120138

Gnomad AFR exome AF: 0.350

Gnomad AMR exome AF: 0.234

Gnomad ASJ exome AF: 0.415

Gnomad EAS exome AF: 0.332

Gnomad SAS exome AF: 0.419

Gnomad FIN exome AF: 0.339

Gnomad NFE exome AF: 0.406

Gnomad OTH exome AF: 0.377

GnomAD4 exome AF: 0.402 AC: 573894 AN: 1428064 Hom.: 116106 Cov.: 35 AF XY: 0.402 AC XY: 284736 AN XY: 707552

Gnomad4 AFR exome AF: 0.354

Gnomad4 AMR exome AF: 0.243

Gnomad4 ASJ exome AF: 0.410

Gnomad4 EAS exome AF: 0.344

Gnomad4 SAS exome AF: 0.413

Gnomad4 FIN exome AF: 0.342

Gnomad4 NFE exome AF: 0.414

Gnomad4 OTH exome AF: 0.397

GnomAD4 genome AF: 0.373 AC: 56783 AN: 152088 Hom.: 10832 Cov.: 32 AF XY: 0.371 AC XY: 27550 AN XY: 74344

Gnomad4 AFR AF: 0.351

Gnomad4 AMR AF: 0.291

Gnomad4 ASJ AF: 0.404

Gnomad4 EAS AF: 0.332

Gnomad4 SAS AF: 0.405

Gnomad4 FIN AF: 0.344

Gnomad4 NFE AF: 0.408

Gnomad4 OTH AF: 0.341

Alfa AF: 0.386 Hom.: 7190

Bravo AF: 0.366

TwinsUK AF: 0.431 AC: 1597

ALSPAC AF: 0.424 AC: 1635

ESP6500AA AF: 0.362 AC: 1597

ESP6500EA AF: 0.404 AC: 3474

ExAC AF: 0.370 AC: 44807

Asia WGS AF: 0.359 AC: 1250 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	14
DANN	Benign	0.22
DEOGEN2	Benign	0.024	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.48	T
MetaRNN	Benign	0.022	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.37	N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	7.9	N
REVEL	Benign	0.21
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.018	B
Vest4		0.039
MPC		0.17
ClinPred		0.0017	T
GERP RS		2.7
Varity_R		0.11
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000072
dbscSNV1_RF	Benign	0.0
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

LitVar

Other links and lift over

dbSNP: rs2161468; hg19: chr19-10088271; COSMIC: COSV53407275;