rs200858199

chr2-227309228-G-Achr2-227309228-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000091.5(COL4A3):c.4665G>A(p.Ala1555=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00313 in 1,614,162 control chromosomes in the GnomAD database, including 11 homozygotes. 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. A1555A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0029 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0032 (9 hom.)
• Consequence: COL4A3 NM_000091.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.484

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 2-227309228-G-A is Benign according to our data. Variant chr2-227309228-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 254999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227309228-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.484 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00287 (437/152306) while in subpopulation AMR AF= 0.00641 (98/15290). AF 95% confidence interval is 0.00538. There are 2 homozygotes in gnomad4. There are 192 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A3	NM_000091.5	c.4665G>A	p.Ala1555=	synonymous_variant	50/52	ENST00000396578.8
MFF-DT	NR_102371.1	n.48-3573C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A3	ENST00000396578.8	c.4665G>A	p.Ala1555=	synonymous_variant	50/52	1	NM_000091.5	P1
MFF-DT	ENST00000439598.6	n.48-3573C>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.00286 AC: 436 AN: 152188 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.0340

Gnomad AMR AF: 0.00642

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00292

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00341

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00241 AC: 601 AN: 249510 Hom.: 3 AF XY: 0.00246 AC XY: 333 AN XY: 135362

Gnomad AFR exome AF: 0.000581

Gnomad AMR exome AF: 0.00328

Gnomad ASJ exome AF: 0.000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.00167

Gnomad NFE exome AF: 0.00348

Gnomad OTH exome AF: 0.00429

GnomAD4 exome AF: 0.00316 AC: 4617 AN: 1461856 Hom.: 9 Cov.: 32 AF XY: 0.00309 AC XY: 2250 AN XY: 727230

Gnomad4 AFR exome AF: 0.000597

Gnomad4 AMR exome AF: 0.00320

Gnomad4 ASJ exome AF: 0.00111

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000499

Gnomad4 FIN exome AF: 0.00185

Gnomad4 NFE exome AF: 0.00369

Gnomad4 OTH exome AF: 0.00286

GnomAD4 genome AF: 0.00287 AC: 437 AN: 152306 Hom.: 2 Cov.: 33 AF XY: 0.00258 AC XY: 192 AN XY: 74480

Gnomad4 AFR AF: 0.000674

Gnomad4 AMR AF: 0.00641

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00292

Gnomad4 NFE AF: 0.00342

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00143 Hom.: 0

Bravo AF: 0.00360

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00365

EpiControl AF: 0.00397

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:7

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	COL4A3: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 22, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 26, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2019	- -

Alport syndrome Benign:2

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Feb 24, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
Cadd	Benign	0.12
Dann	Benign	0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs200858199; hg19: chr2-228173944; COSMIC: COSV67417289; COSMIC: COSV67417289;