rs183218622

Variant names:

• chr2-227310913-C-T
• rs183218622
• NM_000091.5:c.4893C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_000091.5(COL4A3):​c.4893C>T​(p.Phe1631Phe) variant causes a synonymous change. The variant allele was found at a frequency of 0.0039 in 1,614,020 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0032 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0040 (17 hom.)
• Consequence: COL4A3 NM_000091.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: 5.85
• Publications: 2 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.19).
• BP6: Variant 2-227310913-C-T is Benign according to our data. Variant chr2-227310913-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 255002.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00322 (491/152284) while in subpopulation NFE AF = 0.005 (340/68028). AF 95% confidence interval is 0.00456. There are 5 homozygotes in GnomAd4. There are 237 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR,AD,SD gene

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.4893C>T	p.Phe1631Phe	synonymous	Exon 51 of 52	NP_000082.2	Q01955-1
	MFF-DT	NR_102371.1		n.48-5258G>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.4893C>T	p.Phe1631Phe	synonymous	Exon 51 of 52	ENSP00000379823.3	Q01955-1
	COL4A3	ENST00000469504.2	TSL:1	n.*218C>T		non_coding_transcript_exon	Exon 5 of 6	ENSP00000493493.1	A0A2R8Y2F0
	COL4A3	ENST00000469504.2	TSL:1	n.*218C>T		3_prime_UTR	Exon 5 of 6	ENSP00000493493.1	A0A2R8Y2F0

Frequencies

GnomAD3 genomes AF: 0.00323 AC: 491 AN: 152166 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00896

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00500

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.00322 AC: 802 AN: 249162 AF XY: 0.00319

Gnomad AFR exome AF: 0.000518

Gnomad AMR exome AF: 0.0000870

Gnomad ASJ exome AF: 0.00229

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00872

Gnomad NFE exome AF: 0.00503

Gnomad OTH exome AF: 0.00182

GnomAD4 exome AF: 0.00397 AC: 5801 AN: 1461736 Hom.: 17 Cov.: 32 AF XY: 0.00383 AC XY: 2784 AN XY: 727164

African (AFR) AF: 0.000568 AC: 19 AN: 33474

American (AMR) AF: 0.000179 AC: 8 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00172 AC: 45 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00778 AC: 415 AN: 53364

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 0.00465 AC: 5167 AN: 1111978

Other (OTH) AF: 0.00243 AC: 147 AN: 60390

GnomAD4 genome AF: 0.00322 AC: 491 AN: 152284 Hom.: 5 Cov.: 33 AF XY: 0.00318 AC XY: 237 AN XY: 74456

African (AFR) AF: 0.000481 AC: 20 AN: 41552

American (AMR) AF: 0.000196 AC: 3 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00896 AC: 95 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00500 AC: 340 AN: 68028

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00377 Hom.: 2

Bravo AF: 0.00256

EpiCase AF: 0.00267

EpiControl AF: 0.00379

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.19
CADD	Benign	12
DANN	Benign	0.88
PhyloP100		5.9
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs183218622; hg19: chr2-228175629;