rs115757151

chr2-227269899-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000091.5(COL4A3):c.1505-11T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00163 in 1,613,354 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0088 (21 hom., cov: 32)
  • Exomes 𝑓: 0.00088 (24 hom.)
• Consequence: COL4A3 NM_000091.5 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.005061
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0100

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 2-227269899-T-C is Benign according to our data. Variant chr2-227269899-T-C is described in ClinVar as [Benign]. Clinvar id is 254983.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00876 (1334/152302) while in subpopulation AFR AF= 0.0306 (1272/41568). AF 95% confidence interval is 0.0292. There are 21 homozygotes in gnomad4. There are 657 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 21 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A3	NM_000091.5	c.1505-11T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000396578.8
MFF-DT	NR_102371.1	n.423-1130A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A3	ENST00000396578.8	c.1505-11T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000091.5	P1
MFF-DT	ENST00000439598.6	n.423-1130A>G		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.00871 AC: 1325 AN: 152184 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.0305

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00767

GnomAD3 exomes AF: 0.00222 AC: 554 AN: 249292 Hom.: 10 AF XY: 0.00180 AC XY: 243 AN XY: 135246

Gnomad AFR exome AF: 0.0317

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000981

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00166

GnomAD4 exome AF: 0.000883 AC: 1290 AN: 1461052 Hom.: 24 Cov.: 30 AF XY: 0.000707 AC XY: 514 AN XY: 726884

Gnomad4 AFR exome AF: 0.0315

Gnomad4 AMR exome AF: 0.00143

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.00214

GnomAD4 genome AF: 0.00876 AC: 1334 AN: 152302 Hom.: 21 Cov.: 32 AF XY: 0.00882 AC XY: 657 AN XY: 74464

Gnomad4 AFR AF: 0.0306

Gnomad4 AMR AF: 0.00288

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00759

Alfa AF: 0.00443 Hom.: 1

Bravo AF: 0.0101

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 03, 2020	Variant summary: COL4A3 c.1505-11T>C alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 3/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0022 in 249292 control chromosomes, predominantly at a frequency of 0.032 within the African or African-American subpopulation in the gnomAD database, including 10 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 16 fold of the estimated maximal expected allele frequency for a pathogenic variant in COL4A3 causing Alport Syndrome, autosomal recessive phenotype (0.002), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.1505-11T>C in individuals affected with Alport Syndrome, autosomal recessive and no experimental evidence demonstrating its impact on protein function have been reported. One ClinVar submitter (evaluation after 2014) cite the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	c.1505-11T>C in intron 23 of COL4A3: This variant is not expected to have clinic al significance because a T>C change at this position does not diverge from the splice consensus sequence and is therefore unlikely to impact splicing. It has b een identified in 3.00% (290/9672) of African chromosomes by the Exome Aggregati on Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs115757151). -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 16, 2019	- -

Alport syndrome Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
Cadd	Benign	8.8
Dann	Benign	0.64

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0051
dbscSNV1_RF	Benign	0.14
SpliceAI score (max)		0.39		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.39		Position offset: 11

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

Publications

LitVar

Other links and lift over

dbSNP: rs115757151; hg19: chr2-228134615;