rs2229817

Variant names:

• chr9-134835104-C-T
• rs2229817
• NM_000093.5:c.5270C>T
• COL5A1 p.Thr1757Met

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000093.5(COL5A1):​c.5270C>T​(p.Thr1757Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00488 in 1,613,724 control chromosomes in the GnomAD database, including 211 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T1757T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0050 (26 hom., cov: 33)
  • Exomes 𝑓: 0.0049 (185 hom.)
• Consequence: COL5A1 NM_000093.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 2.33
• Publications: 14 publications found

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]

COL5A1 Gene-Disease associations (from GenCC):

• Ehlers-Danlos syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• Ehlers-Danlos syndrome, classic type

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Ambry Genetics, ClinGen
• Ehlers-Danlos syndrome, classic type, 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• arterial disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

LOC101448202 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0027009249).
• BP6: Variant 9-134835104-C-T is Benign according to our data. Variant chr9-134835104-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0849 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000093.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A1	NM_000093.5	MANE Select	c.5270C>T	p.Thr1757Met	missense	Exon 65 of 66	NP_000084.3
	COL5A1	NM_001278074.1		c.5270C>T	p.Thr1757Met	missense	Exon 65 of 66	NP_001265003.1	P20908-2
	LOC101448202	NR_103451.2		n.71-14895G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A1	ENST00000371817.8	TSL:1 MANE Select	c.5270C>T	p.Thr1757Met	missense	Exon 65 of 66	ENSP00000360882.3	P20908-1
	COL5A1	ENST00000371820.4	TSL:2	c.5270C>T	p.Thr1757Met	missense	Exon 65 of 66	ENSP00000360885.4	P20908-2
	COL5A1	ENST00000950240.1		c.5261C>T	p.Thr1754Met	missense	Exon 65 of 66	ENSP00000620299.1

Frequencies

GnomAD3 genomes AF: 0.00505 AC: 768 AN: 152212 Hom.: 27 Cov.: 33

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.0913

Gnomad SAS AF: 0.0217

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000897

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.0120 AC: 3016 AN: 250710 AF XY: 0.0117

Gnomad AFR exome AF: 0.000803

Gnomad AMR exome AF: 0.00958

Gnomad ASJ exome AF: 0.0166

Gnomad EAS exome AF: 0.0878

Gnomad FIN exome AF: 0.000325

Gnomad NFE exome AF: 0.000812

Gnomad OTH exome AF: 0.00916

GnomAD4 exome AF: 0.00486 AC: 7105 AN: 1461394 Hom.: 185 Cov.: 33 AF XY: 0.00529 AC XY: 3849 AN XY: 727046

African (AFR) AF: 0.000627 AC: 21 AN: 33480

American (AMR) AF: 0.00863 AC: 386 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0148 AC: 388 AN: 26134

East Asian (EAS) AF: 0.0795 AC: 3156 AN: 39700

South Asian (SAS) AF: 0.0220 AC: 1898 AN: 86258

European-Finnish (FIN) AF: 0.000321 AC: 17 AN: 52942

Middle Eastern (MID) AF: 0.00399 AC: 23 AN: 5768

European-Non Finnish (NFE) AF: 0.000567 AC: 631 AN: 1112002

Other (OTH) AF: 0.00969 AC: 585 AN: 60388

GnomAD4 genome AF: 0.00504 AC: 768 AN: 152330 Hom.: 26 Cov.: 33 AF XY: 0.00569 AC XY: 424 AN XY: 74478

African (AFR) AF: 0.000793 AC: 33 AN: 41588

American (AMR) AF: 0.00261 AC: 40 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0127 AC: 44 AN: 3470

East Asian (EAS) AF: 0.0917 AC: 474 AN: 5170

South Asian (SAS) AF: 0.0211 AC: 102 AN: 4832

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000897 AC: 61 AN: 68022

Other (OTH) AF: 0.00568 AC: 12 AN: 2114

Alfa AF: 0.00467 Hom.: 35

Bravo AF: 0.00530

Asia WGS AF: 0.0750 AC: 264 AN: 3478

EpiCase AF: 0.00136

EpiControl AF: 0.000948

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	3	not provided (3)
-	-	2	Ehlers-Danlos syndrome, classic type, 1 (2)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	Ehlers-Danlos syndrome type 7A (1)
-	-	1	Ehlers-Danlos syndrome, classic type (1)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)
-	-	1	Fibromuscular dysplasia, multifocal (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		2.3
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.45
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.044	D
Varity_R		0.32
gMVP		0.49
Mutation Taster		=83/17	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2229817;

hg19: chr9-137726950;

COSMIC: COSV65669124;

COSMIC: COSV65669124;