rs10205042

Variant names:

• chr2-227263824-C-T
• rs10205042
• NM_000091.5:c.1195C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-227263824-C-T
• chr2-227263824-C-A
• chr2-227263824-C-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000091.5(COL4A3):​c.1195C>T​(p.Leu399Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.751 in 1,613,536 control chromosomes in the GnomAD database, including 456,799 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. L399L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.73 (40860 hom., cov: 32)
  • Exomes 𝑓: 0.75 (415939 hom.)
• Consequence: COL4A3 NM_000091.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.664
• Publications: 29 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 2-227263824-C-T is Benign according to our data. Variant chr2-227263824-C-T is described in ClinVar as Benign. ClinVar VariationId is 254976.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.664 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.856 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000091.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A3	NM_000091.5	MANE Select	c.1195C>T	p.Leu399Leu	synonymous	Exon 21 of 52	NP_000082.2	Q01955-1
	MFF-DT	NR_102371.1		n.1486+845G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A3	ENST00000396578.8	TSL:1 MANE Select	c.1195C>T	p.Leu399Leu	synonymous	Exon 21 of 52	ENSP00000379823.3	Q01955-1
	MFF-DT	ENST00000439598.6	TSL:1	n.1486+845G>A		intron	N/A
	COL4A3	ENST00000871618.1		c.1195C>T	p.Leu399Leu	synonymous	Exon 21 of 52	ENSP00000541677.1

Frequencies

GnomAD3 genomes AF: 0.732 AC: 111237 AN: 151988 Hom.: 40817 Cov.: 32

Gnomad AFR AF: 0.673

Gnomad AMI AF: 0.574

Gnomad AMR AF: 0.769

Gnomad ASJ AF: 0.638

Gnomad EAS AF: 0.878

Gnomad SAS AF: 0.817

Gnomad FIN AF: 0.800

Gnomad MID AF: 0.623

Gnomad NFE AF: 0.741

Gnomad OTH AF: 0.686

GnomAD2 exomes AF: 0.768 AC: 191130 AN: 248780 AF XY: 0.766

Gnomad AFR exome AF: 0.670

Gnomad AMR exome AF: 0.846

Gnomad ASJ exome AF: 0.637

Gnomad EAS exome AF: 0.884

Gnomad FIN exome AF: 0.798

Gnomad NFE exome AF: 0.737

Gnomad OTH exome AF: 0.744

GnomAD4 exome AF: 0.753 AC: 1100520 AN: 1461430 Hom.: 415939 Cov.: 48 AF XY: 0.753 AC XY: 547225 AN XY: 727030

African (AFR) AF: 0.667 AC: 22329 AN: 33468

American (AMR) AF: 0.837 AC: 37436 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.642 AC: 16783 AN: 26132

East Asian (EAS) AF: 0.868 AC: 34447 AN: 39690

South Asian (SAS) AF: 0.806 AC: 69531 AN: 86242

European-Finnish (FIN) AF: 0.795 AC: 42430 AN: 53380

Middle Eastern (MID) AF: 0.649 AC: 3744 AN: 5768

European-Non Finnish (NFE) AF: 0.745 AC: 828511 AN: 1111656

Other (OTH) AF: 0.750 AC: 45309 AN: 60380

GnomAD4 genome AF: 0.732 AC: 111337 AN: 152106 Hom.: 40860 Cov.: 32 AF XY: 0.736 AC XY: 54731 AN XY: 74364

African (AFR) AF: 0.673 AC: 27914 AN: 41478

American (AMR) AF: 0.769 AC: 11772 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.638 AC: 2215 AN: 3470

East Asian (EAS) AF: 0.878 AC: 4546 AN: 5180

South Asian (SAS) AF: 0.816 AC: 3930 AN: 4814

European-Finnish (FIN) AF: 0.800 AC: 8462 AN: 10574

Middle Eastern (MID) AF: 0.633 AC: 186 AN: 294

European-Non Finnish (NFE) AF: 0.741 AC: 50343 AN: 67972

Other (OTH) AF: 0.685 AC: 1447 AN: 2112

Alfa AF: 0.720 Hom.: 18021

Bravo AF: 0.726

Asia WGS AF: 0.808 AC: 2813 AN: 3478

EpiCase AF: 0.713

EpiControl AF: 0.718

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	2	Alport syndrome (2)
-	-	2	not provided (2)
-	-	1	Autosomal dominant Alport syndrome (1)
-	-	1	Autosomal recessive Alport syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	1.9
DANN	Benign	0.76
PhyloP100		-0.66
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10205042; hg19: chr2-228128540; COSMIC: COSV108247715; COSMIC: COSV108247715;