chr2-227270915-C-T

Variant names:

• chr2-227270915-C-T
• rs28381984
• NM_000091.5:c.1721C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PM1 BP6_Very_Strong BA1

The NM_000091.5(COL4A3):​c.1721C>T​(p.Pro574Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.479 in 1,613,562 control chromosomes in the GnomAD database, including 189,564 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P574P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.39 (13008 hom., cov: 31)
  • Exomes 𝑓: 0.49 (176556 hom.)
• Consequence: COL4A3 NM_000091.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 2.57
• Publications: 47 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 -14 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, 6 uncertain in NM_000091.5
• BP6: Variant 2-227270915-C-T is Benign according to our data. Variant chr2-227270915-C-T is described in ClinVar as Benign. ClinVar VariationId is 254985.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.557 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A3	NM_000091.5	c.1721C>T	p.Pro574Leu	missense_variant	Exon 25 of 52	ENST00000396578.8	NP_000082.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A3	ENST00000396578.8	c.1721C>T	p.Pro574Leu	missense_variant	Exon 25 of 52	1	NM_000091.5	ENSP00000379823.3

Frequencies

GnomAD3 genomes AF: 0.394 AC: 59799 AN: 151772 Hom.: 13014 Cov.: 31

Gnomad AFR AF: 0.193

Gnomad AMI AF: 0.333

Gnomad AMR AF: 0.405

Gnomad ASJ AF: 0.422

Gnomad EAS AF: 0.471

Gnomad SAS AF: 0.576

Gnomad FIN AF: 0.463

Gnomad MID AF: 0.382

Gnomad NFE AF: 0.483

Gnomad OTH AF: 0.391

GnomAD2 exomes AF: 0.469 AC: 116885 AN: 249312 AF XY: 0.478

Gnomad AFR exome AF: 0.182

Gnomad AMR exome AF: 0.469

Gnomad ASJ exome AF: 0.431

Gnomad EAS exome AF: 0.462

Gnomad FIN exome AF: 0.465

Gnomad NFE exome AF: 0.482

Gnomad OTH exome AF: 0.458

GnomAD4 exome AF: 0.488 AC: 713093 AN: 1461670 Hom.: 176556 Cov.: 53 AF XY: 0.490 AC XY: 356514 AN XY: 727148

African (AFR) AF: 0.188 AC: 6290 AN: 33480

American (AMR) AF: 0.463 AC: 20714 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.436 AC: 11389 AN: 26132

East Asian (EAS) AF: 0.481 AC: 19078 AN: 39698

South Asian (SAS) AF: 0.586 AC: 50517 AN: 86256

European-Finnish (FIN) AF: 0.469 AC: 25062 AN: 53398

Middle Eastern (MID) AF: 0.411 AC: 2373 AN: 5768

European-Non Finnish (NFE) AF: 0.495 AC: 549845 AN: 1111830

Other (OTH) AF: 0.461 AC: 27825 AN: 60390

GnomAD4 genome AF: 0.394 AC: 59807 AN: 151892 Hom.: 13008 Cov.: 31 AF XY: 0.395 AC XY: 29273 AN XY: 74198

African (AFR) AF: 0.193 AC: 8013 AN: 41420

American (AMR) AF: 0.406 AC: 6192 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.422 AC: 1461 AN: 3466

East Asian (EAS) AF: 0.470 AC: 2423 AN: 5152

South Asian (SAS) AF: 0.575 AC: 2767 AN: 4816

European-Finnish (FIN) AF: 0.463 AC: 4871 AN: 10524

Middle Eastern (MID) AF: 0.387 AC: 113 AN: 292

European-Non Finnish (NFE) AF: 0.484 AC: 32854 AN: 67948

Other (OTH) AF: 0.385 AC: 810 AN: 2104

Alfa AF: 0.459 Hom.: 53770

Bravo AF: 0.377

TwinsUK AF: 0.500 AC: 1855

ALSPAC AF: 0.497 AC: 1914

ESP6500AA AF: 0.210 AC: 782

ESP6500EA AF: 0.470 AC: 3848

ExAC AF: 0.469 AC: 56654

Asia WGS AF: 0.456 AC: 1586 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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 72% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 67. Only high quality variants are reported. -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 31, 2018

SIB Swiss Institute of Bioinformatics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

This variant is interpreted as a Benign - Stand Alone. The following ACMG Tag(s) were applied: BA1 => Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. -

Apr 28, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 21, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Pro574Leu in exon 25 of COL4A3: This variant is not expected to have clinical significance because it has been identified in 58.90% (9722/16506) of South Asia n chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstit ute.org; dbSNP rs28381984). -

May 09, 2017

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 provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Alport syndrome Benign:2

Mar 04, 2021

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

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
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-1.3	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		2.6
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.017	D
Polyphen		1.0	D
Vest4		0.14
MPC		0.73
ClinPred		0.024	T
GERP RS		5.8
Varity_R		0.18
gMVP		0.55
Mutation Taster		=56/44	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.23		Position offset: 37

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs28381984; hg19: chr2-228135631; COSMIC: COSV67412728;