Genetic Variant NM_000093.5:c.4968C>A (chr9-134825805-C-A) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP7

The NM_000093.5(COL5A1):c.4968C>A(p.Val1656Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,459,144 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. Synonymous variant affecting the same amino acid position (i.e. V1656V) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

COL5A1
NM_000093.5 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0380

Publications

0 publications found

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 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

COL5A1 links:

LOC101448202 (HGNC:):

LOC101448202 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.22).

BP7

Synonymous conserved (PhyloP=0.038 with no splicing effect.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
COL5A1	NM_000093.5	MANE Select	c.4968C>A	p.Val1656Val	synonymous	Exon 63 of 66	NP_000084.3
COL5A1	NM_001278074.1		c.4968C>A	p.Val1656Val	synonymous	Exon 63 of 66	NP_001265003.1
LOC101448202	NR_103451.2		n.71-5596G>T		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
COL5A1	ENST00000371817.8	TSL:1 MANE Select	c.4968C>A	p.Val1656Val	synonymous	Exon 63 of 66	ENSP00000360882.3
COL5A1	ENST00000371820.4	TSL:2	c.4968C>A	p.Val1656Val	synonymous	Exon 63 of 66	ENSP00000360885.4
COL5A1	ENST00000950240.1		c.4959C>A	p.Val1653Val	synonymous	Exon 63 of 66	ENSP00000620299.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1459144

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

725924

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

33412

American (AMR)

AF:

0.00

AC:

AN:

44644

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26086

East Asian (EAS)

AF:

0.00

AC:

AN:

39606

South Asian (SAS)

AF:

0.0000465

AC:

AN:

86074

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53156

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110160

Other (OTH)

AF:

0.00

AC:

AN:

60250

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.22

CADD

Benign

1.6

(source)

DANN

Benign

0.71

PhyloP100

0.038

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over