chr2-227254194-A-G

Position:

• chr2-227254194-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000091.5(COL4A3):​c.828+20A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0462 in 1,603,438 control chromosomes in the GnomAD database, including 5,152 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (2264 hom., cov: 32)
  • Exomes 𝑓: 0.039 (2888 hom.)
• Consequence: COL4A3 NM_000091.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.66

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=-0.9).
• BP6: Variant 2-227254194-A-G is Benign according to our data. Variant chr2-227254194-A-G is described in ClinVar as [Benign]. Clinvar id is 255007.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227254194-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.321 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A3	NM_000091.5	c.828+20A>G		intron_variant		ENST00000396578.8	NP_000082.2
MFF-DT	NR_102371.1	n.1592+4984T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A3	ENST00000396578.8	c.828+20A>G		intron_variant		1	NM_000091.5	ENSP00000379823	P1
MFF-DT	ENST00000439598.6	n.1592+4984T>C		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.118 AC: 17979 AN: 151864 Hom.: 2249 Cov.: 32

Gnomad AFR AF: 0.326

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0552

Gnomad ASJ AF: 0.0752

Gnomad EAS AF: 0.0680

Gnomad SAS AF: 0.0433

Gnomad FIN AF: 0.0661

Gnomad MID AF: 0.0541

Gnomad NFE AF: 0.0290

Gnomad OTH AF: 0.0844

GnomAD3 exomes AF: 0.0580 AC: 14441 AN: 249070 Hom.: 1115 AF XY: 0.0521 AC XY: 7034 AN XY: 135124

Gnomad AFR exome AF: 0.333

Gnomad AMR exome AF: 0.0358

Gnomad ASJ exome AF: 0.0772

Gnomad EAS exome AF: 0.0673

Gnomad SAS exome AF: 0.0364

Gnomad FIN exome AF: 0.0626

Gnomad NFE exome AF: 0.0292

Gnomad OTH exome AF: 0.0530

GnomAD4 exome AF: 0.0387 AC: 56114 AN: 1451462 Hom.: 2888 Cov.: 29 AF XY: 0.0376 AC XY: 27211 AN XY: 722890

Gnomad4 AFR exome AF: 0.331

Gnomad4 AMR exome AF: 0.0380

Gnomad4 ASJ exome AF: 0.0767

Gnomad4 EAS exome AF: 0.103

Gnomad4 SAS exome AF: 0.0367

Gnomad4 FIN exome AF: 0.0560

Gnomad4 NFE exome AF: 0.0251

Gnomad4 OTH exome AF: 0.0527

GnomAD4 genome AF: 0.119 AC: 18025 AN: 151976 Hom.: 2264 Cov.: 32 AF XY: 0.118 AC XY: 8729 AN XY: 74272

Gnomad4 AFR AF: 0.326

Gnomad4 AMR AF: 0.0551

Gnomad4 ASJ AF: 0.0752

Gnomad4 EAS AF: 0.0684

Gnomad4 SAS AF: 0.0423

Gnomad4 FIN AF: 0.0661

Gnomad4 NFE AF: 0.0290

Gnomad4 OTH AF: 0.0835

Alfa AF: 0.0782 Hom.: 348

Bravo AF: 0.127

Asia WGS AF: 0.0690 AC: 242 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 21, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Autosomal recessive Alport syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jun 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.024
DANN	Benign	0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs13386404; hg19: chr2-228118910; COSMIC: COSV67415786;