Genetic Variant NM_033380.3:c.2057delC (chrX-108601898-TC-T) – ACMG Classification: Pathogenic (18 pts)

Variant summary

Our verdict is . The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_033380.3(COL4A5):c.2057delC(p.Pro686GlnfsTer50) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

COL4A5
NM_033380.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 5.54

Publications

2 publications found

Variant links:

Genes affected

COL4A5 (HGNC:2207): (collagen type IV alpha 5 chain) This gene encodes one of the six subunits of type IV collagen, the major structural component of basement membranes. Mutations in this gene are associated with X-linked Alport syndrome, also known as hereditary nephritis. Like the other members of the type IV collagen gene family, this gene is organized in a head-to-head conformation with another type IV collagen gene so that each gene pair shares a common promoter. Alternatively spliced transcript variants have been identified for this gene. [provided by RefSeq, Aug 2010]

COL4A5 Gene-Disease associations (from GenCC):

Alport syndrome
Inheritance: XL Classification: DEFINITIVE Submitted by: G2P, ClinGen
X-linked Alport syndrome
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Myriad Women's Health, Labcorp Genetics (formerly Invitae)

COL4A5 links:

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new If you want to explore the variant's impact on the transcript NM_033380.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant X-108601898-TC-T is Pathogenic according to our data. Variant chrX-108601898-TC-T is described in ClinVar as Pathogenic. ClinVar VariationId is 24482.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033380.3. 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
	COL4A5	NM_033380.3	MANE Select	c.2057delC	p.Pro686GlnfsTer50	frameshift	Exon 27 of 53	NP_203699.1	P29400-2
	COL4A5	NM_000495.5		c.2057delC	p.Pro686GlnfsTer50	frameshift	Exon 27 of 51	NP_000486.1	P29400-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COL4A5	ENST00000328300.11	TSL:1 MANE Select	c.2057delC	p.Pro686GlnfsTer50	frameshift	Exon 27 of 53	ENSP00000331902.7	P29400-2
COL4A5	ENST00000483338.1	TSL:1	c.881delC	p.Pro294GlnfsTer50	frameshift	Exon 11 of 20	ENSP00000495685.1	Q49AM6
COL4A5	ENST00000949143.1		c.2057delC	p.Pro686GlnfsTer50	frameshift	Exon 27 of 51	ENSP00000619202.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1041803

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

327173

African (AFR)

AF:

0.00

AC:

AN:

25074

American (AMR)

AF:

0.00

AC:

AN:

29731

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18530

East Asian (EAS)

AF:

0.00

AC:

AN:

28391

South Asian (SAS)

AF:

0.00

AC:

AN:

50020

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38280

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3951

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

803847

Other (OTH)

AF:

0.00

AC:

AN:

43979

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

X-linked Alport syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

5.5

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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