rs77176843

Variant names:

• chr9-134817837-G-A
• rs77176843
• NM_000093.5:c.4230+6G>A

Your query was ambiguous. Multiple possible variants found:

• chr9-134817837-G-A
• chr9-134817837-G-C
• chr9-134817837-G-T

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.4230+6G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0344 in 1,601,504 control chromosomes in the GnomAD database, including 1,179 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (91 hom., cov: 33)
  • Exomes 𝑓: 0.035 (1088 hom.)
• Consequence: COL5A1 NM_000093.5 splice_region, intron
• Scores: Splicing: ADA: 0.00002806
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.132
• Publications: 5 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=-0.85).
• BP6: Variant 9-134817837-G-A is Benign according to our data. Variant chr9-134817837-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136893.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0259 (3947/152350) while in subpopulation NFE AF = 0.0412 (2805/68036). AF 95% confidence interval is 0.04. There are 91 homozygotes in GnomAd4. There are 1867 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3947 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.4230+6G>A		splice_region intron	N/A	NP_000084.3
	COL5A1	NM_001278074.1		c.4230+6G>A		splice_region intron	N/A	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.4230+6G>A		splice_region intron	N/A	ENSP00000360882.3	P20908-1
	COL5A1	ENST00000371820.4	TSL:2	c.4230+6G>A		splice_region intron	N/A	ENSP00000360885.4	P20908-2
	COL5A1	ENST00000950240.1		c.4221+6G>A		splice_region intron	N/A	ENSP00000620299.1

Frequencies

GnomAD3 genomes AF: 0.0259 AC: 3945 AN: 152232 Hom.: 91 Cov.: 33

Gnomad AFR AF: 0.00782

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0158

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00475

Gnomad FIN AF: 0.0441

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0412

Gnomad OTH AF: 0.0186

GnomAD2 exomes AF: 0.0255 AC: 5684 AN: 222540 AF XY: 0.0250

Gnomad AFR exome AF: 0.00589

Gnomad AMR exome AF: 0.00988

Gnomad ASJ exome AF: 0.0131

Gnomad EAS exome AF: 0.0000610

Gnomad FIN exome AF: 0.0416

Gnomad NFE exome AF: 0.0413

Gnomad OTH exome AF: 0.0261

GnomAD4 exome AF: 0.0353 AC: 51212 AN: 1449154 Hom.: 1088 Cov.: 33 AF XY: 0.0346 AC XY: 24871 AN XY: 719678

African (AFR) AF: 0.00502 AC: 167 AN: 33248

American (AMR) AF: 0.0103 AC: 442 AN: 42876

Ashkenazi Jewish (ASJ) AF: 0.0122 AC: 316 AN: 25870

East Asian (EAS) AF: 0.0000512 AC: 2 AN: 39080

South Asian (SAS) AF: 0.00594 AC: 500 AN: 84204

European-Finnish (FIN) AF: 0.0419 AC: 2203 AN: 52574

Middle Eastern (MID) AF: 0.00417 AC: 24 AN: 5756

European-Non Finnish (NFE) AF: 0.0416 AC: 45953 AN: 1105660

Other (OTH) AF: 0.0268 AC: 1605 AN: 59886

GnomAD4 genome AF: 0.0259 AC: 3947 AN: 152350 Hom.: 91 Cov.: 33 AF XY: 0.0251 AC XY: 1867 AN XY: 74502

African (AFR) AF: 0.00779 AC: 324 AN: 41572

American (AMR) AF: 0.0157 AC: 241 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.0127 AC: 44 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00517 AC: 25 AN: 4834

European-Finnish (FIN) AF: 0.0441 AC: 469 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0412 AC: 2805 AN: 68036

Other (OTH) AF: 0.0184 AC: 39 AN: 2114

Alfa AF: 0.0334 Hom.: 52

Bravo AF: 0.0220

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	Ehlers-Danlos syndrome, classic type, 1 (2)
-	-	2	not provided (2)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	Ehlers-Danlos syndrome type 7A (1)
-	-	1	Fibromuscular dysplasia, multifocal (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	6.4
DANN	Benign	0.41
PhyloP100		-0.13
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000028
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.010		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: rs77176843; hg19: chr9-137709683; COSMIC: COSV65674178;