chr2-227253440-T-A

Variant names:

• chr2-227253440-T-A
• rs55997063
• NM_000091.5:c.687+103T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000091.5(COL4A3):​c.687+103T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0533 in 1,423,358 control chromosomes in the GnomAD database, including 2,280 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.063 (332 hom., cov: 32)
  • Exomes 𝑓: 0.052 (1948 hom.)
• Consequence: COL4A3 NM_000091.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.421
• Publications: 7 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 2-227253440-T-A is Benign according to our data. Variant chr2-227253440-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1172970.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0815 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A3	NM_000091.5	c.687+103T>A		intron_variant	Intron 12 of 51	ENST00000396578.8	NP_000082.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A3	ENST00000396578.8	c.687+103T>A		intron_variant	Intron 12 of 51	1	NM_000091.5	ENSP00000379823.3

Frequencies

GnomAD3 genomes AF: 0.0624 AC: 9501 AN: 152148 Hom.: 327 Cov.: 32

Gnomad AFR AF: 0.0836

Gnomad AMI AF: 0.0362

Gnomad AMR AF: 0.0570

Gnomad ASJ AF: 0.0983

Gnomad EAS AF: 0.0861

Gnomad SAS AF: 0.0752

Gnomad FIN AF: 0.0497

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0481

Gnomad OTH AF: 0.0753

GnomAD2 exomes AF: 0.0591 AC: 14724 AN: 249346 AF XY: 0.0603

Gnomad AFR exome AF: 0.0841

Gnomad AMR exome AF: 0.0363

Gnomad ASJ exome AF: 0.100

Gnomad EAS exome AF: 0.0910

Gnomad FIN exome AF: 0.0474

Gnomad NFE exome AF: 0.0491

Gnomad OTH exome AF: 0.0605

GnomAD4 exome AF: 0.0522 AC: 66346 AN: 1271090 Hom.: 1948 Cov.: 18 AF XY: 0.0533 AC XY: 34287 AN XY: 642940

African (AFR) AF: 0.0845 AC: 2505 AN: 29654

American (AMR) AF: 0.0381 AC: 1697 AN: 44492

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 2540 AN: 24946

East Asian (EAS) AF: 0.0882 AC: 3417 AN: 38756

South Asian (SAS) AF: 0.0831 AC: 6835 AN: 82234

European-Finnish (FIN) AF: 0.0477 AC: 2545 AN: 53360

Middle Eastern (MID) AF: 0.0816 AC: 441 AN: 5406

European-Non Finnish (NFE) AF: 0.0460 AC: 43121 AN: 938156

Other (OTH) AF: 0.0600 AC: 3245 AN: 54086

GnomAD4 genome AF: 0.0626 AC: 9528 AN: 152268 Hom.: 332 Cov.: 32 AF XY: 0.0638 AC XY: 4748 AN XY: 74458

African (AFR) AF: 0.0838 AC: 3483 AN: 41544

American (AMR) AF: 0.0569 AC: 871 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0983 AC: 341 AN: 3470

East Asian (EAS) AF: 0.0861 AC: 446 AN: 5180

South Asian (SAS) AF: 0.0751 AC: 362 AN: 4822

European-Finnish (FIN) AF: 0.0497 AC: 528 AN: 10624

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0481 AC: 3272 AN: 68012

Other (OTH) AF: 0.0806 AC: 170 AN: 2110

Alfa AF: 0.0621 Hom.: 59

Bravo AF: 0.0648

Asia WGS AF: 0.0940 AC: 326 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Autosomal recessive Alport syndrome Benign:1

Jun 10, 2021

Genome-Nilou Lab

Significance: Likely 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	-0.82
CADD	Benign	3.2
DANN	Benign	0.61
PhyloP100		0.42
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: rs55997063; hg19: chr2-228118156; COSMIC: COSV67414076;