19-9977595-C-G

Variant names:

• chr19-9977595-C-G
• rs2161468
• NM_015719.4:c.3125G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong 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. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on 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. R1042W) has been classified as Uncertain significance.

• 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
• Publications: 28 publications found

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]

ENSG00000295554 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.021603942).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.404 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015719.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A3	NM_015719.4	MANE Select	c.3125G>C	p.Arg1042Pro	missense splice_region	Exon 42 of 67	NP_056534.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A3	ENST00000264828.4	TSL:1 MANE Select	c.3125G>C	p.Arg1042Pro	missense splice_region	Exon 42 of 67	ENSP00000264828.3
	ENSG00000295554	ENST00000730923.1		n.74-6455C>G		intron	N/A

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

GnomAD2 exomes AF: 0.368 AC: 82232 AN: 223238 AF XY: 0.377

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 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

African (AFR) AF: 0.354 AC: 11494 AN: 32496

American (AMR) AF: 0.243 AC: 9666 AN: 39824

Ashkenazi Jewish (ASJ) AF: 0.410 AC: 9781 AN: 23840

East Asian (EAS) AF: 0.344 AC: 13543 AN: 39316

South Asian (SAS) AF: 0.413 AC: 33440 AN: 80940

European-Finnish (FIN) AF: 0.342 AC: 17896 AN: 52326

Middle Eastern (MID) AF: 0.347 AC: 1931 AN: 5572

European-Non Finnish (NFE) AF: 0.414 AC: 452801 AN: 1094894

Other (OTH) AF: 0.397 AC: 23342 AN: 58856

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

African (AFR) AF: 0.351 AC: 14583 AN: 41516

American (AMR) AF: 0.291 AC: 4455 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.404 AC: 1401 AN: 3470

East Asian (EAS) AF: 0.332 AC: 1707 AN: 5144

South Asian (SAS) AF: 0.405 AC: 1954 AN: 4828

European-Finnish (FIN) AF: 0.344 AC: 3649 AN: 10600

Middle Eastern (MID) AF: 0.405 AC: 119 AN: 294

European-Non Finnish (NFE) AF: 0.408 AC: 27731 AN: 67910

Other (OTH) AF: 0.341 AC: 722 AN: 2116

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 v4.9

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
PhyloP100		3.9
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
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

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