rs41306397

chr9-134699909-C-Achr9-134699909-C-Gchr9-134699909-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_000093.5(COL5A1):c.278C>A(p.Ala93Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,230 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/23 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. A93V) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: COL5A1 NM_000093.5 missense, splice_region
• Scores: Splicing: ADA: 0.0006737
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.31

Genes affected

COL5A1 (HGNC:2209): (collagen type V alpha 1 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. The encoded procollagen protein occurs commonly as the heterotrimer pro-alpha1(V)-pro-alpha1(V)-pro-alpha2(V). Mutations in this gene are associated with Ehlers-Danlos syndrome, types I and II. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, COL5A1
• BP4: Computational evidence support a benign effect (MetaRNN=0.09949535).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL5A1	NM_000093.5	c.278C>A	p.Ala93Glu	missense_variant, splice_region_variant	3/66	ENST00000371817.8
COL5A1	NM_001278074.1	c.278C>A	p.Ala93Glu	missense_variant, splice_region_variant	3/66
COL5A1	XM_017014266.3	c.278C>A	p.Ala93Glu	missense_variant, splice_region_variant	3/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL5A1	ENST00000371817.8	c.278C>A	p.Ala93Glu	missense_variant, splice_region_variant	3/66	1	NM_000093.5	P4
COL5A1	ENST00000371820.4	c.278C>A	p.Ala93Glu	missense_variant, splice_region_variant	3/66	2		A2
COL5A1	ENST00000464187.1	n.700C>A		splice_region_variant, non_coding_transcript_exon_variant	4/6	2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152230 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152230 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74380

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
Cadd	Benign	16
Dann	Benign	0.95
DEOGEN2	Benign	0.089	T;.
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.76	T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.099	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.55	N;N
MutationTaster	Benign	0.96	N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	0.44	N;.
REVEL	Benign	0.060
Sift	Benign	0.083	T;.
Sift4G	Benign	0.22	T;T
Polyphen		0.011	B;.
Vest4		0.18
MutPred		0.49		Gain of solvent accessibility (P = 0.0145);Gain of solvent accessibility (P = 0.0145);
MVP		0.10
MPC		0.20
ClinPred		0.20	T
GERP RS		3.9
Varity_R		0.037
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00067
dbscSNV1_RF	Benign	0.012
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: rs41306397; hg19: chr9-137591755;