rs115324397

chr2-227245975-C-Achr2-227245975-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000091.5(COL4A3):c.346C>A(p.Pro116Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00807 in 1,613,656 control chromosomes in the GnomAD database, including 80 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0051 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0084 (74 hom.)
• Consequence: COL4A3 NM_000091.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 2.58

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 -18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000091.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.016165346).
• BP6: Variant 2-227245975-C-A is Benign according to our data. Variant chr2-227245975-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 254994.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227245975-C-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00509 (776/152308) while in subpopulation NFE AF= 0.00888 (604/68024). AF 95% confidence interval is 0.00829. There are 6 homozygotes in gnomad4. There are 342 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A3	NM_000091.5	c.346C>A	p.Pro116Thr	missense_variant	6/52	ENST00000396578.8
MFF-DT	NR_102371.1	n.1593-7801G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A3	ENST00000396578.8	c.346C>A	p.Pro116Thr	missense_variant	6/52	1	NM_000091.5	P1
MFF-DT	ENST00000439598.6	n.1593-7801G>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.00511 AC: 778 AN: 152188 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00179

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00889

Gnomad OTH AF: 0.00573

GnomAD3 exomes AF: 0.00485 AC: 1209 AN: 249440 Hom.: 6 AF XY: 0.00480 AC XY: 650 AN XY: 135330

Gnomad AFR exome AF: 0.00220

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000490

Gnomad FIN exome AF: 0.00394

Gnomad NFE exome AF: 0.00878

Gnomad OTH exome AF: 0.00545

GnomAD4 exome AF: 0.00838 AC: 12246 AN: 1461348 Hom.: 74 Cov.: 30 AF XY: 0.00804 AC XY: 5847 AN XY: 727000

Gnomad4 AFR exome AF: 0.00158

Gnomad4 AMR exome AF: 0.00177

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000557

Gnomad4 FIN exome AF: 0.00358

Gnomad4 NFE exome AF: 0.0103

Gnomad4 OTH exome AF: 0.00639

GnomAD4 genome AF: 0.00509 AC: 776 AN: 152308 Hom.: 6 Cov.: 33 AF XY: 0.00459 AC XY: 342 AN XY: 74476

Gnomad4 AFR AF: 0.00178

Gnomad4 AMR AF: 0.00393

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00226

Gnomad4 NFE AF: 0.00888

Gnomad4 OTH AF: 0.00567

Alfa AF: 0.00706 Hom.: 4

Bravo AF: 0.00546

TwinsUK AF: 0.00890 AC: 33

ALSPAC AF: 0.0101 AC: 39

ESP6500AA AF: 0.00338 AC: 13

ESP6500EA AF: 0.0110 AC: 91

ExAC AF: 0.00500 AC: 604

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00605

EpiControl AF: 0.00741

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 13, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 17, 2021	The p.Pro116Thr variant in COL4A3 is classified as benign because it has been identified in 0.9% (1119/128642) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported as benign and likely benign in ClinVar (Variation ID 254994). ACMG/AMP criteria applied: BA1, BP4. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 08, 2018	Variant summary: The COL4A3 c.346C>A (p.Pro116Thr) variant involves the alteration of a conserved nucleotide located in the Collagen triple helix repeat domain of the protein (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 1348/277088 control chromosomes (7 homozygotes), predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.008757 (1109/126648). This frequency is about 4 times the estimated maximal expected allele frequency of a pathogenic COL4A3 variant (0.0020412), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. This variant has been reported in multiple affected individuals without stong evidence for causality. In addition, one other clinical diagnostic laboratory classified this variant as benign. Taken together, this variant is classified as likely benign. -

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	COL4A3: BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 17, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 25, 2018	This variant is associated with the following publications: (PMID: 24854265, 14871398, 30245029, 29924831) -

Alport syndrome Benign:2

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 14, 2019	- -

Chronic kidney disease Benign:1

Likely benign, criteria provided, single submitter

research

Cavalleri Lab, Royal College of Surgeons in Ireland

May 28, 2020

PP3, BP6, BS1 -

Focal segmental glomerulosclerosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Aug 24, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.16
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.61	D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.016	T
MetaSVM	Uncertain	0.76	D
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.50
Sift	Uncertain	0.027	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.45
MVP		0.91
MPC		0.78
ClinPred		0.013	T
GERP RS		5.2
Varity_R		0.20
gMVP		0.27

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: rs115324397; hg19: chr2-228110691;