NM_000093.5:c.-110A>G

Variant names:

• chr9-134642078-A-G
• rs180741151
• NM_000093.5:c.-110A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000093.5(COL5A1):​c.-110A>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0078 in 973,184 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0084 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0077 (36 hom.)
• Consequence: COL5A1 NM_000093.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.530
• Publications: 1 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: Genomics England PanelApp, Ambry Genetics, ClinGen, Orphanet
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 9-134642078-A-G is Benign according to our data. Variant chr9-134642078-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 365703.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00839 (1274/151846) while in subpopulation AMR AF = 0.00937 (143/15268). AF 95% confidence interval is 0.00812. There are 9 homozygotes in GnomAd4. There are 630 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1274 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.-110A>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 66	NP_000084.3
	COL5A1	NM_000093.5	MANE Select	c.-110A>G		5_prime_UTR	Exon 1 of 66	NP_000084.3
	COL5A1	NM_001278074.1		c.-110A>G		5_prime_UTR_premature_start_codon_gain	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.-110A>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 66	ENSP00000360882.3	P20908-1
	COL5A1	ENST00000371817.8	TSL:1 MANE Select	c.-110A>G		5_prime_UTR	Exon 1 of 66	ENSP00000360882.3	P20908-1
	COL5A1	ENST00000371820.4	TSL:2	c.-110A>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 66	ENSP00000360885.4	P20908-2

Frequencies

GnomAD3 genomes AF: 0.00840 AC: 1274 AN: 151736 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00745

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.00938

Gnomad ASJ AF: 0.0251

Gnomad EAS AF: 0.000591

Gnomad SAS AF: 0.00518

Gnomad FIN AF: 0.0102

Gnomad MID AF: 0.0195

Gnomad NFE AF: 0.00823

Gnomad OTH AF: 0.0153

GnomAD4 exome AF: 0.00770 AC: 6321 AN: 821338 Hom.: 36 Cov.: 11 AF XY: 0.00777 AC XY: 3062 AN XY: 394320

African (AFR) AF: 0.00877 AC: 158 AN: 18010

American (AMR) AF: 0.00617 AC: 49 AN: 7944

Ashkenazi Jewish (ASJ) AF: 0.0212 AC: 266 AN: 12550

East Asian (EAS) AF: 0.00 AC: 0 AN: 25180

South Asian (SAS) AF: 0.00365 AC: 53 AN: 14520

European-Finnish (FIN) AF: 0.00896 AC: 188 AN: 20984

Middle Eastern (MID) AF: 0.0260 AC: 64 AN: 2460

European-Non Finnish (NFE) AF: 0.00759 AC: 5197 AN: 684922

Other (OTH) AF: 0.00995 AC: 346 AN: 34768

GnomAD4 genome AF: 0.00839 AC: 1274 AN: 151846 Hom.: 9 Cov.: 32 AF XY: 0.00849 AC XY: 630 AN XY: 74228

African (AFR) AF: 0.00743 AC: 308 AN: 41464

American (AMR) AF: 0.00937 AC: 143 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.0251 AC: 87 AN: 3470

East Asian (EAS) AF: 0.000593 AC: 3 AN: 5056

South Asian (SAS) AF: 0.00518 AC: 25 AN: 4822

European-Finnish (FIN) AF: 0.0102 AC: 108 AN: 10562

Middle Eastern (MID) AF: 0.0208 AC: 6 AN: 288

European-Non Finnish (NFE) AF: 0.00823 AC: 559 AN: 67896

Other (OTH) AF: 0.0152 AC: 32 AN: 2112

Alfa AF: 0.00815 Hom.: 1

Bravo AF: 0.00832

Asia WGS AF: 0.00348 AC: 12 AN: 3458

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Ehlers-Danlos syndrome type 7A (1)
-	-	1	Ehlers-Danlos syndrome, classic type (1)
-	-	1	Ehlers-Danlos syndrome, classic type, 1 (1)
-	-	1	Fibromuscular dysplasia, multifocal (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	14
DANN	Benign	0.92
PhyloP100		-0.53
PromoterAI		0.010	Neutral
Mutation Taster		=299/1	polymorphism

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: rs180741151; hg19: chr9-137533924;