chr9-134641824-G-T

Variant names:

• chr9-134641824-G-T
• rs780212970
• NM_000093.5:c.-364G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000093.5(COL5A1):​c.-364G>T 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 0.00000425 in 235,396 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: COL5A1 NM_000093.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.10
• 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: 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).

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.-364G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 66	NP_000084.3
	COL5A1	NM_000093.5	MANE Select	c.-364G>T		5_prime_UTR	Exon 1 of 66	NP_000084.3
	COL5A1	NM_001278074.1		c.-364G>T		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.-364G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 66	ENSP00000360882.3	P20908-1
	COL5A1	ENST00000371817.8	TSL:1 MANE Select	c.-364G>T		5_prime_UTR	Exon 1 of 66	ENSP00000360882.3	P20908-1
	COL5A1	ENST00000371820.4	TSL:2	c.-364G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 66	ENSP00000360885.4	P20908-2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000425 AC: 1 AN: 235396 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 119630

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 6636

American (AMR) AF: 0.00 AC: 0 AN: 7048

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8704

East Asian (EAS) AF: 0.00 AC: 0 AN: 22230

South Asian (SAS) AF: 0.000445 AC: 1 AN: 2246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20486

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1246

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 151256

Other (OTH) AF: 0.00 AC: 0 AN: 15544

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	19
DANN	Benign	0.97
PhyloP100		1.1
PromoterAI		0.050	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: rs780212970; hg19: chr9-137533670;