rs4436947

Positions:

• chr2-227308362-A-G
• chr2-227308362-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000091.5(COL4A3):​c.4462+443A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 1 in 152,300 control chromosomes in the GnomAD database, including 76,090 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 1.0 (76090 hom., cov: 31)
• Consequence: COL4A3 NM_000091.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.29

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.06).
• BP6: Variant 2-227308362-A-G is Benign according to our data. Variant chr2-227308362-A-G is described in ClinVar as [Benign]. Clinvar id is 585521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A3	NM_000091.5	c.4462+443A>G		intron_variant		ENST00000396578.8	NP_000082.2
MFF-DT	NR_102371.1	n.48-2707T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A3	ENST00000396578.8	c.4462+443A>G		intron_variant		1	NM_000091.5	ENSP00000379823	P1
MFF-DT	ENST00000439598.6	n.48-2707T>C		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 1.00 AC: 152122 AN: 152182 Hom.: 76031 Cov.: 31

Gnomad AFR AF: 1.00

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.999

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.999

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

GnomAD4 genome AF: 1.00 AC: 152240 AN: 152300 Hom.: 76090 Cov.: 31 AF XY: 1.00 AC XY: 74443 AN XY: 74472

Gnomad4 AFR AF: 1.00

Gnomad4 AMR AF: 0.999

Gnomad4 ASJ AF: 1.00

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 1.00

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 0.999

Gnomad4 OTH AF: 0.999

Alfa AF: 0.999 Hom.: 8658

Bravo AF: 0.999

Asia WGS AF: 1.00 AC: 3478 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 23, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.71
DANN	Benign	0.47

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

Publications

LitVar

Other links and lift over

dbSNP: rs4436947; hg19: chr2-228173078;