2-227270464-A-G

Variant names:

• chr2-227270464-A-G
• rs7606754
• NM_000091.5:c.1576-306A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000091.5(COL4A3):​c.1576-306A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.687 in 152,080 control chromosomes in the GnomAD database, including 36,233 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.69 (36233 hom., cov: 33)
• Consequence: COL4A3 NM_000091.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0210
• Publications: 29 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 2-227270464-A-G is Benign according to our data. Variant chr2-227270464-A-G is described in ClinVar as Benign. ClinVar VariationId is 1241250.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.791 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A3	NM_000091.5	c.1576-306A>G		intron_variant	Intron 24 of 51	ENST00000396578.8	NP_000082.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A3	ENST00000396578.8	c.1576-306A>G		intron_variant	Intron 24 of 51	1	NM_000091.5	ENSP00000379823.3

Frequencies

GnomAD3 genomes AF: 0.687 AC: 104361 AN: 151962 Hom.: 36183 Cov.: 33

Gnomad AFR AF: 0.798

Gnomad AMI AF: 0.547

Gnomad AMR AF: 0.605

Gnomad ASJ AF: 0.653

Gnomad EAS AF: 0.580

Gnomad SAS AF: 0.738

Gnomad FIN AF: 0.624

Gnomad MID AF: 0.680

Gnomad NFE AF: 0.656

Gnomad OTH AF: 0.662

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

GnomAD4 genome AF: 0.687 AC: 104470 AN: 152080 Hom.: 36233 Cov.: 33 AF XY: 0.683 AC XY: 50776 AN XY: 74316

African (AFR) AF: 0.798 AC: 33117 AN: 41504

American (AMR) AF: 0.604 AC: 9233 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.653 AC: 2265 AN: 3468

East Asian (EAS) AF: 0.579 AC: 2999 AN: 5178

South Asian (SAS) AF: 0.737 AC: 3557 AN: 4824

European-Finnish (FIN) AF: 0.624 AC: 6582 AN: 10542

Middle Eastern (MID) AF: 0.697 AC: 205 AN: 294

European-Non Finnish (NFE) AF: 0.656 AC: 44615 AN: 67970

Other (OTH) AF: 0.663 AC: 1398 AN: 2110

Alfa AF: 0.667 Hom.: 69598

Bravo AF: 0.688

Asia WGS AF: 0.647 AC: 2250 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	6.2
DANN	Benign	0.78
PhyloP100		0.021
Mutation Taster		=100/0	polymorphism (auto)

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: rs7606754; hg19: chr2-228135180;