Genetic Variant NM_000093.5:c.-180C>A (chr9-134642008-C-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000093.5(COL5A1):c.-180C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0122 in 523,310 control chromosomes in the GnomAD database, including 60 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 17 hom., cov: 32)

Exomes 𝑓: 0.012 ( 43 hom. )

Consequence

COL5A1
NM_000093.5 5_prime_UTR

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.973

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.52).

BP6

Variant 9-134642008-C-A is Benign according to our data. Variant chr9-134642008-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 1200990.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 = 0.0127 (1925/151868) while in subpopulation AMR AF= 0.0142 (217/15280). AF 95% confidence interval is 0.013. There are 17 homozygotes in gnomad4. There are 940 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1925 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
COL5A1	NM_000093.5 link	c.-180C>A	5_prime_UTR_variant	Exon 1 of 66	ENST00000371817.8	NP_000084.3	P20908-1A0A024R8E5B2ZZ86Q59EE7
COL5A1	NM_001278074.1 link	c.-180C>A	5_prime_UTR_variant	Exon 1 of 66		NP_001265003.1	B2ZZ86Q59EE7
COL5A1	XM_017014266.3 link	c.-180C>A	5_prime_UTR_variant	Exon 1 of 65		XP_016869755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817 link	c.-180C>A		5_prime_UTR_variant	Exon 1 of 66	1	NM_000093.5	ENSP00000360882.3		P20908-1
COL5A1	ENST00000371820 link	c.-180C>A		5_prime_UTR_variant	Exon 1 of 66	2		ENSP00000360885.4		P20908-2H7BY82

Frequencies

GnomAD3 genomes

AF:

0.0127

AC:

1924

AN:

151760

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0115

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0142

Gnomad ASJ

AF:

0.0153

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00187

Gnomad FIN

AF:

0.0185

Gnomad MID

AF:

0.0226

Gnomad NFE

AF:

0.0137

Gnomad OTH

AF:

0.0168

GnomAD4 exome

AF:

0.0120

AC:

4459

AN:

371442

Hom.:

Cov.:

AF XY:

0.0120

AC XY:

2208

AN XY:

184706

show subpopulations

Gnomad4 AFR exome

AF:

0.0120

Gnomad4 AMR exome

AF:

0.0105

Gnomad4 ASJ exome

AF:

0.0148

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000894

Gnomad4 FIN exome

AF:

0.0163

Gnomad4 NFE exome

AF:

0.0127

Gnomad4 OTH exome

AF:

0.0131

GnomAD4 genome

AF:

0.0127

AC:

1925

AN:

151868

Hom.:

Cov.:

AF XY:

0.0127

AC XY:

940

AN XY:

74226

show subpopulations

Gnomad4 AFR

AF:

0.0115

Gnomad4 AMR

AF:

0.0142

Gnomad4 ASJ

AF:

0.0153

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00208

Gnomad4 FIN

AF:

0.0185

Gnomad4 NFE

AF:

0.0137

Gnomad4 OTH

AF:

0.0166

Alfa

AF:

0.0145

Hom.:

Bravo

AF:

0.0117

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 26, 2018

GeneDx

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

-0.52

CADD

Benign

DANN

Benign

0.96

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over