NM_000091.5:c.21C>T

Variant names:

• chr2-227164747-C-T
• rs530353117
• NM_000091.5:c.21C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_000091.5(COL4A3):​c.21C>T​(p.Pro7Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000291 in 1,375,162 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. P7P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: COL4A3 NM_000091.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.59
• 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]

COL4A3 Gene-Disease associations (from GenCC):

• Alport syndrome 3b, autosomal recessive

  Inheritance: AR, AD Classification: DEFINITIVE Submitted by: G2P
• autosomal recessive Alport syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Laboratory for Molecular Medicine, Genomics England PanelApp, Orphanet
• Alport syndrome

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal dominant Alport syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• hematuria, benign familial, 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 2-227164747-C-T is Benign according to our data. Variant chr2-227164747-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2870067.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.59 with no splicing effect.

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.21C>T	p.Pro7Pro	synonymous	Exon 1 of 52	NP_000082.2	Q01955-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A3	ENST00000396578.8	TSL:1 MANE Select	c.21C>T	p.Pro7Pro	synonymous	Exon 1 of 52	ENSP00000379823.3	Q01955-1
	COL4A3	ENST00000871618.1		c.21C>T	p.Pro7Pro	synonymous	Exon 1 of 52	ENSP00000541677.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000291 AC: 4 AN: 1375162 Hom.: 0 Cov.: 31 AF XY: 0.00000147 AC XY: 1 AN XY: 678358

African (AFR) AF: 0.00 AC: 0 AN: 30268

American (AMR) AF: 0.00 AC: 0 AN: 35460

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24926

East Asian (EAS) AF: 0.00 AC: 0 AN: 34938

South Asian (SAS) AF: 0.00 AC: 0 AN: 78596

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33430

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4052

European-Non Finnish (NFE) AF: 0.00000279 AC: 3 AN: 1076088

Other (OTH) AF: 0.0000174 AC: 1 AN: 57404

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	3.1
DANN	Benign	0.79
PhyloP100		-1.6
PromoterAI		0.084	Neutral
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs530353117; hg19: chr2-228029463;