rs1306992119

chr2-227280529-ACTCCCTGGACTTCCAGGT-Achr2-227280529-ACTCCCTGGACTTCCAGGT-ACTCCCTGGACTTCCAGGTCTCCCTGGACTTCCAGGT

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PM4 PP5_Very_Strong

The NM_000091.5(COL4A3):c.2323_2340del(p.Leu775_Gly780del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.00000205 in 1,461,808 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L772L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: COL4A3 NM_000091.5 inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 6.50

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 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000091.5.
• PP5: Variant 2-227280529-ACTCCCTGGACTTCCAGGT-A is Pathogenic according to our data. Variant chr2-227280529-ACTCCCTGGACTTCCAGGT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 556542.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227280529-ACTCCCTGGACTTCCAGGT-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A3	NM_000091.5	c.2323_2340del	p.Leu775_Gly780del	inframe_deletion	30/52	ENST00000396578.8
MFF-DT	NR_102371.1	n.330-972_330-955del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A3	ENST00000396578.8	c.2323_2340del	p.Leu775_Gly780del	inframe_deletion	30/52	1	NM_000091.5	P1
MFF-DT	ENST00000439598.6	n.330-972_330-955del		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461808 Hom.: 0 AF XY: 0.00000275 AC XY: 2 AN XY: 727200

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive Alport syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Feb 06, 2018

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jun 22, 2023

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the COL4A3 protein in which other variant(s) (p.Gly777Asp) have been determined to be pathogenic (PMID: 26633401, 27904025). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 556542). This variant has been observed in individual(s) with Alport syndrome (PMID: 24052634, 24854265, 28780565). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This variant, c.2323_2340del, results in the deletion of 6 amino acid(s) of the COL4A3 protein (p.Leu775_Gly780del), but otherwise preserves the integrity of the reading frame. -

Benign familial hematuria;C4746547:Autosomal dominant Alport syndrome;C4746745:Autosomal recessive Alport syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 25, 2022

- -

Hematuria Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Sydney Genome Diagnostics, Children's Hospital Westmead

Aug 28, 2018

This patient is heterozygous for the c.2323_2340del (p.Leu775_Gly780del) variant in exon 30 of the COL4A3 gene. This variant results in an inframe deletion of six amino acid residues (Leu-Pro-Gly-Leu-Pro-Gly) in the triple helical domain of the alpha 3 chain of type IV collagen. To our knowledge, this nucleotide variant has not been previously reported. However, a variant involving an inframe deletion of the same six amino acids, c.2313_2330del (p.Leu775_Gly780del), has been previously reported in trans with another pathogenic COL4A3 variant in a patient with autosomal recessive Alport syndrome in the literature (Storey et al 2013 J Am Soc Nephrol 24:1945-1954). This variant is likely to be pathogenic as an inframe deletion of six amino acids is likely to disrupt the folding of the triple helix domain. -

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: rs1306992119; hg19: chr2-228145245;