NM_000091.5:c.1370_1378delTAGGGTCTC

Variant names:

• chr2-227266468-ATCTAGGGTC-A
• rs1553755767
• NM_000091.5:c.1370_1378delTAGGGTCTC

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM4 PP5

The NM_000091.5(COL4A3):​c.1370_1378delTAGGGTCTC​(p.Leu457_Ser459del) variant causes a disruptive inframe deletion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. L457L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL4A3 NM_000091.5 disruptive_inframe_deletion
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.96
• Publications: 0 publications found

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

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 9 uncertain in NM_000091.5
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000091.5.
• PP5: Variant 2-227266468-ATCTAGGGTC-A is Pathogenic according to our data. Variant chr2-227266468-ATCTAGGGTC-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 558060.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000091.5. 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
	COL4A3	NM_000091.5	MANE Select	c.1370_1378delTAGGGTCTC	p.Leu457_Ser459del	disruptive_inframe_deletion	Exon 22 of 52	NP_000082.2
	MFF-DT	NR_102371.1		n.656-542_656-534delGACCCTAGA		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A3	ENST00000396578.8	TSL:1 MANE Select	c.1370_1378delTAGGGTCTC	p.Leu457_Ser459del	disruptive_inframe_deletion	Exon 22 of 52	ENSP00000379823.3
	MFF-DT	ENST00000439598.6	TSL:1	n.656-542_656-534delGACCCTAGA		intron	N/A
	COL4A3	ENST00000871618.1		c.1370_1378delTAGGGTCTC	p.Leu457_Ser459del	disruptive_inframe_deletion	Exon 22 of 52	ENSP00000541677.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Autosomal recessive Alport syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.0

Splicing

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

Other links and lift over

dbSNP: rs1553755767; hg19: chr2-228131184;