chr9-134641939-G-A

Variant names:

• chr9-134641939-G-A
• rs574222596
• NM_000093.5:c.-249G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000093.5(COL5A1):​c.-249G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 390,184 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0030 (3 hom., cov: 34)
  • Exomes 𝑓: 0.00032 (0 hom.)
• Consequence: COL5A1 NM_000093.5 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.395
• Publications: 0 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: ClinGen, Orphanet, PanelApp Australia, Genomics England PanelApp, Ambry Genetics
• 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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 9-134641939-G-A is Benign according to our data. Variant chr9-134641939-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1199542.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00298 (452/151906) while in subpopulation AFR AF = 0.0106 (440/41464). AF 95% confidence interval is 0.00979. There are 3 homozygotes in GnomAd4. There are 217 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High AC in GnomAd4 at 452 AD gene.

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.-249G>A		5_prime_UTR	Exon 1 of 66	NP_000084.3
	COL5A1	NM_001278074.1		c.-249G>A		5_prime_UTR	Exon 1 of 66	NP_001265003.1	P20908-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A1	ENST00000371817.8	TSL:1 MANE Select	c.-249G>A		5_prime_UTR	Exon 1 of 66	ENSP00000360882.3	P20908-1
	COL5A1	ENST00000371820.4	TSL:2	c.-249G>A		5_prime_UTR	Exon 1 of 66	ENSP00000360885.4	P20908-2
	COL5A1	ENST00000950240.1		c.-249G>A		upstream_gene	N/A	ENSP00000620299.1

Frequencies

GnomAD3 genomes AF: 0.00297 AC: 451 AN: 151796 Hom.: 3 Cov.: 34

Gnomad AFR AF: 0.0106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000959

GnomAD4 exome AF: 0.000319 AC: 76 AN: 238278 Hom.: 0 Cov.: 0 AF XY: 0.000280 AC XY: 34 AN XY: 121248

African (AFR) AF: 0.00864 AC: 58 AN: 6716

American (AMR) AF: 0.000847 AC: 6 AN: 7086

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8706

East Asian (EAS) AF: 0.00 AC: 0 AN: 22458

South Asian (SAS) AF: 0.00 AC: 0 AN: 2992

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1242

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 152888

Other (OTH) AF: 0.000769 AC: 12 AN: 15610

GnomAD4 genome AF: 0.00298 AC: 452 AN: 151906 Hom.: 3 Cov.: 34 AF XY: 0.00292 AC XY: 217 AN XY: 74248

African (AFR) AF: 0.0106 AC: 440 AN: 41464

American (AMR) AF: 0.000589 AC: 9 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5092

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67856

Other (OTH) AF: 0.000949 AC: 2 AN: 2108

Alfa AF: 0.00257 Hom.: 1

Bravo AF: 0.00313

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	17
DANN	Uncertain	0.98
PhyloP100		0.40
PromoterAI		-0.030	Neutral

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

Other links and lift over

dbSNP: rs574222596; hg19: chr9-137533785;