NM_000093.5:c.3852+47A>T

Variant names:

• chr9-134812759-A-T
• rs111564392
• NM_000093.5:c.3852+47A>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_000093.5(COL5A1):​c.3852+47A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000778 in 969,632 control chromosomes in the GnomAD database, including 1 homozygotes. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0000082 (0 hom., cov: 28)
  • Exomes 𝑓: 0.00089 (1 hom.)
• Consequence: COL5A1 NM_000093.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -4.91
• 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: ClinGen, Orphanet, Ambry Genetics, PanelApp Australia, Genomics England PanelApp
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 9-134812759-A-T is Benign according to our data. Variant chr9-134812759-A-T is described in ClinVar as Benign. ClinVar VariationId is 255083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A1	NM_000093.5	MANE Select	c.3852+47A>T		intron	N/A	NP_000084.3
	COL5A1	NM_001278074.1		c.3852+47A>T		intron	N/A	NP_001265003.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A1	ENST00000371817.8	TSL:1 MANE Select	c.3852+47A>T		intron	N/A	ENSP00000360882.3
	COL5A1	ENST00000371820.4	TSL:2	c.3852+47A>T		intron	N/A	ENSP00000360885.4

Frequencies

GnomAD3 genomes AF: 0.00000817 AC: 1 AN: 122374 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000173

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000889 AC: 753 AN: 847258 Hom.: 1 Cov.: 12 AF XY: 0.000804 AC XY: 347 AN XY: 431812

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

African (AFR) AF: 0.00118 AC: 20 AN: 16964

American (AMR) AF: 0.0000309 AC: 1 AN: 32388

Ashkenazi Jewish (ASJ) AF: 0.000211 AC: 4 AN: 18984

East Asian (EAS) AF: 0.0000644 AC: 2 AN: 31074

South Asian (SAS) AF: 0.000231 AC: 14 AN: 60568

European-Finnish (FIN) AF: 0.0000504 AC: 2 AN: 39664

Middle Eastern (MID) AF: 0.000694 AC: 2 AN: 2882

European-Non Finnish (NFE) AF: 0.00111 AC: 675 AN: 606620

Other (OTH) AF: 0.000866 AC: 33 AN: 38114

⚠️ 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 AF: 0.00000817 AC: 1 AN: 122374 Hom.: 0 Cov.: 28 AF XY: 0.0000167 AC XY: 1 AN XY: 59798

African (AFR) AF: 0.00 AC: 0 AN: 28290

American (AMR) AF: 0.00 AC: 0 AN: 13512

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2852

East Asian (EAS) AF: 0.00 AC: 0 AN: 4664

South Asian (SAS) AF: 0.00 AC: 0 AN: 3866

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8672

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 270

European-Non Finnish (NFE) AF: 0.0000173 AC: 1 AN: 57726

Other (OTH) AF: 0.00 AC: 0 AN: 1722

Alfa AF: 0.0149 Hom.: 1

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.095
DANN	Benign	0.45
PhyloP100		-4.9
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs111564392; hg19: chr9-137704605;