rs778043831
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000092.5(COL4A4):βc.2638delGβ(p.Ala880HisfsTer70) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,612,618 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000092.5 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152006Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 249178Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 135292
GnomAD4 exome AF: 0.0000205 AC: 30AN: 1460612Hom.: 0 Cov.: 32 AF XY: 0.0000275 AC XY: 20AN XY: 726724
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152006Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74268
ClinVar
Submissions by phenotype
Alport syndrome Pathogenic:2
This sequence change in COL4A4 is a frameshift variant predicted to cause a premature stop codon, p.(Ala880Hisfs*70), in biologically relevant exon 31/48 leading to nonsense-mediated decay in a gene in which loss of function is an established disease mechanism (PMID: 20301386). The highest population minor allele frequency in the population database gnomAD v2.1 is 0.01% (2/15,438 alleles) in the African/African American population. This variant has been detected in at least two unrelated individuals with Alport syndrome. Of those individuals, one individual was homozygous and one compound heterozygous for the variant and a pathogenic variant was confirmed in trans by family testing (PMID: 24052634). The variant has been reported to segregate with haematuria in heterozygous individuals from at least two families (PMID: 12325029, 30506145). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PM3, PP1. -
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not provided Pathogenic:2
PM3_strong, PS4_moderate, PVS1 -
This sequence change creates a premature translational stop signal (p.Ala880Hisfs*70) in the COL4A4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COL4A4 are known to be pathogenic (PMID: 21196518, 24854265, 25307543). This variant is present in population databases (rs778043831, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with Alport syndrome (PMID: 12325029, 17216251, 24052634). This variant is also known as 2864delG. ClinVar contains an entry for this variant (Variation ID: 550471). For these reasons, this variant has been classified as Pathogenic. -
Glomerulonephritis Pathogenic:1
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Autosomal recessive Alport syndrome;CN376803:Hematuria, benign familial, 1 Pathogenic:1
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Autosomal recessive Alport syndrome Pathogenic:1
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Hematuria, benign familial, 1 Pathogenic:1
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function is a known mechanism of disease for this gene and is associated with Alport syndrome 2 (MIM#203780 and thin basement membrane nephropathy (MIM#141200). Dominant negative is a suspected mechanism of disease for this gene as it is a structural protein (PMIDs: 12028435, 24046192). (I) 0108 - This gene is associated with both recessive and dominant disease. Alport syndrome typically has biallelic inheritance, although rare cases of monoallelic inheritance have been reported (PMID: 28704582). Thin basement membrane nephropathy (TBMN) and focal segmental glomerulosclerosis (FSGS) are associated with autosomal dominant inheritance (OMIM, PMIDs: 16467446, 17942953). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 (3 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar, and has been observed in individuals with recessive and dominant Alport syndrome (PMIDs: 24052634, 36239278, 17216251). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
COL4A4-related disorder Pathogenic:1
The COL4A4 c.2638delG variant is predicted to result in a frameshift and premature protein termination (p.Ala880Hisfs*70). This variant has been reported to be pathogenic for autosomal recessive Alport syndrome and autosomal dominant thin glomerular basement membrane disease (TBMD) (see for example, Dagher et al. 2002. PubMed ID: 12325029; Jayasinghe et al. 2020. PubMed ID: 32939031, Suppl. Table S2). This variant is reported in 0.013% of alleles in individuals of African descent in gnomAD. Frameshift variants in COL4A4 are expected to be pathogenic. This variant is interpreted as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at