19-9968054-A-G

Position:

• chr19-9968054-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000264828.4(COL5A3):​c.4340T>C​(p.Leu1447Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000695 in 1,438,428 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: COL5A3 ENST00000264828.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.384

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23515856).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL5A3	NM_015719.4	c.4340T>C	p.Leu1447Pro	missense_variant	60/67	ENST00000264828.4	NP_056534.2
COL5A3	XM_011528042.3	c.4337T>C	p.Leu1446Pro	missense_variant	60/67		XP_011526344.1
COL5A3	XM_017026849.2	c.2003T>C	p.Leu668Pro	missense_variant	33/40		XP_016882338.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL5A3	ENST00000264828.4	c.4340T>C	p.Leu1447Pro	missense_variant	60/67	1	NM_015719.4	ENSP00000264828	P1
COL5A3	ENST00000461214.1	n.347T>C		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.95e-7 AC: 1 AN: 1438428 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 715480

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.04e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 21, 2024

The c.4340T>C (p.L1447P) alteration is located in exon 60 (coding exon 60) of the COL5A3 gene. This alteration results from a T to C substitution at nucleotide position 4340, causing the leucine (L) at amino acid position 1447 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.62	D
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	-1.5	N
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-4.3	D
REVEL	Benign	0.26
Sift	Benign	0.12	T
Sift4G	Benign	0.29	T
Polyphen		0.0010	B
Vest4		0.18
MutPred		0.32		Gain of relative solvent accessibility (P = 0.0023);
MVP		0.53
MPC		0.17
ClinPred		0.28	T
GERP RS		4.3
Varity_R		0.54
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-10078730;