2-227253440-T-A

Position:

• chr2-227253440-T-A

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.687+103T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0533 in 1,423,358 control chromosomes in the GnomAD database, including 2,280 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.063 (332 hom., cov: 32)
  • Exomes 𝑓: 0.052 (1948 hom.)
• Consequence: COL4A3 NM_000091.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.421

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=-0.82).
• BP6: Variant 2-227253440-T-A is Benign according to our data. Variant chr2-227253440-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 1172970.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0815 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A3	NM_000091.5	c.687+103T>A		intron_variant		ENST00000396578.8	NP_000082.2
MFF-DT	NR_102371.1	n.1592+5738A>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A3	ENST00000396578.8	c.687+103T>A		intron_variant		1	NM_000091.5	ENSP00000379823	P1
MFF-DT	ENST00000439598.6	n.1592+5738A>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.0624 AC: 9501 AN: 152148 Hom.: 327 Cov.: 32

Gnomad AFR AF: 0.0836

Gnomad AMI AF: 0.0362

Gnomad AMR AF: 0.0570

Gnomad ASJ AF: 0.0983

Gnomad EAS AF: 0.0861

Gnomad SAS AF: 0.0752

Gnomad FIN AF: 0.0497

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0481

Gnomad OTH AF: 0.0753

GnomAD3 exomes AF: 0.0591 AC: 14724 AN: 249346 Hom.: 563 AF XY: 0.0603 AC XY: 8157 AN XY: 135266

Gnomad AFR exome AF: 0.0841

Gnomad AMR exome AF: 0.0363

Gnomad ASJ exome AF: 0.100

Gnomad EAS exome AF: 0.0910

Gnomad SAS exome AF: 0.0843

Gnomad FIN exome AF: 0.0474

Gnomad NFE exome AF: 0.0491

Gnomad OTH exome AF: 0.0605

GnomAD4 exome AF: 0.0522 AC: 66346 AN: 1271090 Hom.: 1948 Cov.: 18 AF XY: 0.0533 AC XY: 34287 AN XY: 642940

Gnomad4 AFR exome AF: 0.0845

Gnomad4 AMR exome AF: 0.0381

Gnomad4 ASJ exome AF: 0.102

Gnomad4 EAS exome AF: 0.0882

Gnomad4 SAS exome AF: 0.0831

Gnomad4 FIN exome AF: 0.0477

Gnomad4 NFE exome AF: 0.0460

Gnomad4 OTH exome AF: 0.0600

GnomAD4 genome AF: 0.0626 AC: 9528 AN: 152268 Hom.: 332 Cov.: 32 AF XY: 0.0638 AC XY: 4748 AN XY: 74458

Gnomad4 AFR AF: 0.0838

Gnomad4 AMR AF: 0.0569

Gnomad4 ASJ AF: 0.0983

Gnomad4 EAS AF: 0.0861

Gnomad4 SAS AF: 0.0751

Gnomad4 FIN AF: 0.0497

Gnomad4 NFE AF: 0.0481

Gnomad4 OTH AF: 0.0806

Alfa AF: 0.0621 Hom.: 59

Bravo AF: 0.0648

Asia WGS AF: 0.0940 AC: 326 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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Autosomal recessive Alport syndrome Benign:1

Likely 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	-0.82
CADD	Benign	3.2
DANN	Benign	0.61

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: rs55997063; hg19: chr2-228118156; COSMIC: COSV67414076;