NM_000091.5:c.888+30G>A

Variant names:

• chr2-227254745-G-A
• rs35467545
• NM_000091.5:c.888+30G>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.888+30G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0839 in 1,533,476 control chromosomes in the GnomAD database, including 6,046 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.076 (575 hom., cov: 32)
  • Exomes 𝑓: 0.085 (5471 hom.)
• Consequence: COL4A3 NM_000091.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.736
• 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=-0.9).
• BP6: Variant 2-227254745-G-A is Benign according to our data. Variant chr2-227254745-G-A is described in ClinVar as Benign. ClinVar VariationId is 682614.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.16 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A3	NM_000091.5	c.888+30G>A		intron_variant	Intron 15 of 51	ENST00000396578.8	NP_000082.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A3	ENST00000396578.8	c.888+30G>A		intron_variant	Intron 15 of 51	1	NM_000091.5	ENSP00000379823.3

Frequencies

GnomAD3 genomes AF: 0.0760 AC: 11558 AN: 152142 Hom.: 570 Cov.: 32

Gnomad AFR AF: 0.0335

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.164

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.155

Gnomad SAS AF: 0.105

Gnomad FIN AF: 0.0380

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0786

Gnomad OTH AF: 0.0908

GnomAD2 exomes AF: 0.0971 AC: 24158 AN: 248786 AF XY: 0.0968

Gnomad AFR exome AF: 0.0338

Gnomad AMR exome AF: 0.172

Gnomad ASJ exome AF: 0.0944

Gnomad EAS exome AF: 0.154

Gnomad FIN exome AF: 0.0370

Gnomad NFE exome AF: 0.0817

Gnomad OTH exome AF: 0.104

GnomAD4 exome AF: 0.0848 AC: 117108 AN: 1381216 Hom.: 5471 Cov.: 23 AF XY: 0.0854 AC XY: 59052 AN XY: 691856

African (AFR) AF: 0.0325 AC: 1036 AN: 31836

American (AMR) AF: 0.172 AC: 7661 AN: 44598

Ashkenazi Jewish (ASJ) AF: 0.0963 AC: 2470 AN: 25644

East Asian (EAS) AF: 0.124 AC: 4861 AN: 39312

South Asian (SAS) AF: 0.110 AC: 9344 AN: 84586

European-Finnish (FIN) AF: 0.0419 AC: 2237 AN: 53334

Middle Eastern (MID) AF: 0.106 AC: 599 AN: 5638

European-Non Finnish (NFE) AF: 0.0803 AC: 83422 AN: 1038606

Other (OTH) AF: 0.0950 AC: 5478 AN: 57662

GnomAD4 genome AF: 0.0760 AC: 11578 AN: 152260 Hom.: 575 Cov.: 32 AF XY: 0.0771 AC XY: 5739 AN XY: 74452

African (AFR) AF: 0.0335 AC: 1391 AN: 41552

American (AMR) AF: 0.165 AC: 2520 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 364 AN: 3468

East Asian (EAS) AF: 0.155 AC: 802 AN: 5184

South Asian (SAS) AF: 0.106 AC: 510 AN: 4822

European-Finnish (FIN) AF: 0.0380 AC: 403 AN: 10610

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.0786 AC: 5347 AN: 68020

Other (OTH) AF: 0.0937 AC: 198 AN: 2114

Alfa AF: 0.0823 Hom.: 509

Bravo AF: 0.0841

Asia WGS AF: 0.143 AC: 497 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not specified Benign:1

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 28% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 26. Only high quality variants are reported. -

Autosomal recessive Alport syndrome Benign:1

Jun 10, 2021

Genome-Nilou Lab

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	-0.90
CADD	Benign	0.28
DANN	Benign	0.39
PhyloP100		-0.74
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: rs35467545; hg19: chr2-228119461; COSMIC: COSV107512077;