rs375998368

Variant names:

• chr9-134811605-T-A
• rs375998368
• NM_000093.5:c.3690+6T>A

Your query was ambiguous. Multiple possible variants found:

• chr9-134811605-T-A
• chr9-134811605-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000093.5(COL5A1):​c.3690+6T>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 0.0000696 in 1,551,100 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00036 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: COL5A1 NM_000093.5 splice_region, intron
• Scores: Splicing: ADA: 0.0003899
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.276

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 9-134811605-T-A is Benign according to our data. Variant chr9-134811605-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 386597.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000361 (55/152320) while in subpopulation AFR AF= 0.00123 (51/41580). AF 95% confidence interval is 0.000958. There are 0 homozygotes in gnomad4. There are 26 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 55 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL5A1	NM_000093.5	c.3690+6T>A		splice_region_variant, intron_variant	Intron 46 of 65	ENST00000371817.8	NP_000084.3
COL5A1	NM_001278074.1	c.3690+6T>A		splice_region_variant, intron_variant	Intron 46 of 65		NP_001265003.1
COL5A1	XM_017014266.3	c.3690+6T>A		splice_region_variant, intron_variant	Intron 46 of 64		XP_016869755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8	c.3690+6T>A		splice_region_variant, intron_variant	Intron 46 of 65	1	NM_000093.5	ENSP00000360882.3
COL5A1	ENST00000371820.4	c.3690+6T>A		splice_region_variant, intron_variant	Intron 46 of 65	2		ENSP00000360885.4

Frequencies

GnomAD3 genomes AF: 0.000361 AC: 55 AN: 152202 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000126 AC: 20 AN: 158714 Hom.: 1 AF XY: 0.000131 AC XY: 11 AN XY: 83818

Gnomad AFR exome AF: 0.00202

Gnomad AMR exome AF: 0.0000402

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000223

GnomAD4 exome AF: 0.0000379 AC: 53 AN: 1398780 Hom.: 0 Cov.: 31 AF XY: 0.0000362 AC XY: 25 AN XY: 690574

Gnomad4 AFR exome AF: 0.00133

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000121

GnomAD4 genome AF: 0.000361 AC: 55 AN: 152320 Hom.: 0 Cov.: 33 AF XY: 0.000349 AC XY: 26 AN XY: 74476

Gnomad4 AFR AF: 0.00123

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.000465

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Aug 24, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Aug 03, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ehlers-Danlos syndrome, classic type, 1 Benign:1

Dec 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.65
DANN	Benign	0.70

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00039
dbscSNV1_RF	Benign	0.040
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

Publications

LitVar

Other links and lift over

dbSNP: rs375998368; hg19: chr9-137703451;