rs1553758893

chr2-227277450-T-TATCCCTGG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000091.5(COL4A3):c.2031_2038dup(p.Gly680AspfsTer70) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,446,564 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G674G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: COL4A3 NM_000091.5 frameshift, splice_region
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: -0.0490

Genes affected

COL4A3 (HGNC:2204): (collagen type IV alpha 3 chain) Type IV collagen, the major structural component of basement membranes, is a multimeric protein composed of 3 alpha subunits. These subunits are encoded by 6 different genes, alpha 1 through alpha 6, each of which can form a triple helix structure with 2 other subunits to form type IV collagen. This gene encodes alpha 3. In the Goodpasture syndrome, autoantibodies bind to the collagen molecules in the basement membranes of alveoli and glomeruli. The epitopes that elicit these autoantibodies are localized largely to the non-collagenous C-terminal domain of the protein. A specific kinase phosphorylates amino acids in this same C-terminal region and the expression of this kinase is upregulated during pathogenesis. This gene is also linked to an autosomal recessive form of Alport syndrome. The mutations contributing to this syndrome are also located within the exons that encode this C-terminal region. 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. [provided by RefSeq, Jun 2010]

MFF-DT (HGNC:41067): (MFF divergent transcript)

ACMG classification

Verdict is Pathogenic. Variant got 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 2-227277450-T-TATCCCTGG is Pathogenic according to our data. Variant chr2-227277450-T-TATCCCTGG is described in ClinVar as [Pathogenic]. Clinvar id is 555966.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A3	NM_000091.5	c.2031_2038dup	p.Gly680AspfsTer70	frameshift_variant, splice_region_variant	28/52	ENST00000396578.8
MFF-DT	NR_102371.1	n.422+2032_422+2033insCCAGGGAT		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A3	ENST00000396578.8	c.2031_2038dup	p.Gly680AspfsTer70	frameshift_variant, splice_region_variant	28/52	1	NM_000091.5	P1
MFF-DT	ENST00000439598.6	n.422+2032_422+2033insCCAGGGAT		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000123 AC: 3 AN: 244894 Hom.: 0 AF XY: 0.0000227 AC XY: 3 AN XY: 132442

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000180

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.0000118 AC: 17 AN: 1446564 Hom.: 0 Cov.: 29 AF XY: 0.0000181 AC XY: 13 AN XY: 719996

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000145

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive Alport syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Jan 04, 2018

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2020

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in COL4A3 are known to be pathogenic (PMID: 8956999, 24854265, 26809805, 27281700). This variant has been observed in individual(s) with Alport syndrome (PMID: 24052634). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gly680Aspfs*70) in the COL4A3 gene. It is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553758893; hg19: chr2-228142166;