rs1554781477

chr9-134699936-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PM5 PP2 PP3_Moderate

The NM_000093.5(COL5A1):c.305T>C(p.Ile102Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I102N) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: COL5A1 NM_000093.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.87

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-134699936-T-A is described in Lovd as [Likely_pathogenic].
• PP2: Missense variant where missense usually causes diseases, COL5A1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.882

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL5A1	NM_000093.5	c.305T>C	p.Ile102Thr	missense_variant	3/66	ENST00000371817.8
COL5A1	NM_001278074.1	c.305T>C	p.Ile102Thr	missense_variant	3/66
COL5A1	XM_017014266.3	c.305T>C	p.Ile102Thr	missense_variant	3/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL5A1	ENST00000371817.8	c.305T>C	p.Ile102Thr	missense_variant	3/66	1	NM_000093.5	P4
COL5A1	ENST00000371820.4	c.305T>C	p.Ile102Thr	missense_variant	3/66	2		A2
COL5A1	ENST00000464187.1	n.727T>C		non_coding_transcript_exon_variant	4/6	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 21, 2017

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2022

COL5A1: PM2, PM5 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D;D
M_CAP	Benign	0.018	T
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.8	M;M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.3	D;.
REVEL	Uncertain	0.55
Sift	Uncertain	0.0010	D;.
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.89	P;.
Vest4		0.97
MutPred		0.66		Loss of stability (P = 0.003);Loss of stability (P = 0.003);
MVP		0.81
MPC		0.70
ClinPred		0.97	D
GERP RS		4.8
Varity_R		0.49
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs1554781477; hg19: chr9-137591782;