rs56326869

Positions:

• chr2-227257523-T-C

Variant summary

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

The ENST00000396578.8(COL4A3):​c.988-80T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0253 in 1,165,430 control chromosomes in the GnomAD database, including 533 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (50 hom., cov: 33)
  • Exomes 𝑓: 0.026 (483 hom.)
• Consequence: COL4A3 ENST00000396578.8 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.555

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=-0.83).
• BP6: Variant 2-227257523-T-C is Benign according to our data. Variant chr2-227257523-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 683248.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227257523-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0194 (2960/152332) while in subpopulation NFE AF= 0.0286 (1947/68022). AF 95% confidence interval is 0.0276. There are 50 homozygotes in gnomad4. There are 1395 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 50 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A3	NM_000091.5	c.988-80T>C		intron_variant		ENST00000396578.8	NP_000082.2
MFF-DT	NR_102371.1	n.1592+1655A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A3	ENST00000396578.8	c.988-80T>C		intron_variant		1	NM_000091.5	ENSP00000379823	P1
MFF-DT	ENST00000439598.6	n.1592+1655A>G		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.0195 AC: 2961 AN: 152214 Hom.: 50 Cov.: 33

Gnomad AFR AF: 0.00456

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0180

Gnomad ASJ AF: 0.0809

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0199

Gnomad FIN AF: 0.00979

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0286

Gnomad OTH AF: 0.0230

GnomAD4 exome AF: 0.0261 AC: 26469 AN: 1013098 Hom.: 483 AF XY: 0.0266 AC XY: 13938 AN XY: 524324

Gnomad4 AFR exome AF: 0.00519

Gnomad4 AMR exome AF: 0.0147

Gnomad4 ASJ exome AF: 0.0742

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0218

Gnomad4 FIN exome AF: 0.00908

Gnomad4 NFE exome AF: 0.0287

Gnomad4 OTH exome AF: 0.0299

GnomAD4 genome AF: 0.0194 AC: 2960 AN: 152332 Hom.: 50 Cov.: 33 AF XY: 0.0187 AC XY: 1395 AN XY: 74494

Gnomad4 AFR AF: 0.00457

Gnomad4 AMR AF: 0.0180

Gnomad4 ASJ AF: 0.0809

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0201

Gnomad4 FIN AF: 0.00979

Gnomad4 NFE AF: 0.0286

Gnomad4 OTH AF: 0.0227

Alfa AF: 0.0223 Hom.: 3

Bravo AF: 0.0196

Asia WGS AF: 0.00693 AC: 24 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 2018	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. -

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	-0.83
CADD	Benign	8.8
DANN	Benign	0.76

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: rs56326869; hg19: chr2-228122239;