rs80109666

Variant names:

• chr2-227254151-G-A
• rs80109666
• NM_000091.5:c.805G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-227254151-G-A
• chr2-227254151-G-C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000091.5(COL4A3):​c.805G>A​(p.Glu269Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0118 in 1,613,684 control chromosomes in the GnomAD database, including 734 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. E269E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.029 (164 hom., cov: 32)
  • Exomes 𝑓: 0.010 (570 hom.)
• Consequence: COL4A3 NM_000091.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -1.33
• Publications: 17 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 -18 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000091.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.0018270016).
• BP6: Variant 2-227254151-G-A is Benign according to our data. Variant chr2-227254151-G-A is described in ClinVar as Benign. ClinVar VariationId is 255006.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.135 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.805G>A	p.Glu269Lys	missense	Exon 14 of 52	NP_000082.2	Q01955-1
	MFF-DT	NR_102371.1		n.1592+5027C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A3	ENST00000396578.8	TSL:1 MANE Select	c.805G>A	p.Glu269Lys	missense	Exon 14 of 52	ENSP00000379823.3	Q01955-1
	MFF-DT	ENST00000439598.6	TSL:1	n.1592+5027C>T		intron	N/A
	COL4A3	ENST00000871618.1		c.805G>A	p.Glu269Lys	missense	Exon 14 of 52	ENSP00000541677.1

Frequencies

GnomAD3 genomes AF: 0.0293 AC: 4460 AN: 152098 Hom.: 164 Cov.: 32

Gnomad AFR AF: 0.0672

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0153

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.143

Gnomad SAS AF: 0.0253

Gnomad FIN AF: 0.0271

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00297

Gnomad OTH AF: 0.0230

GnomAD2 exomes AF: 0.0232 AC: 5790 AN: 249418 AF XY: 0.0214

Gnomad AFR exome AF: 0.0694

Gnomad AMR exome AF: 0.00727

Gnomad ASJ exome AF: 0.0142

Gnomad EAS exome AF: 0.153

Gnomad FIN exome AF: 0.0276

Gnomad NFE exome AF: 0.00337

Gnomad OTH exome AF: 0.0182

GnomAD4 exome AF: 0.00999 AC: 14606 AN: 1461468 Hom.: 570 Cov.: 31 AF XY: 0.00994 AC XY: 7226 AN XY: 727076

African (AFR) AF: 0.0711 AC: 2373 AN: 33392

American (AMR) AF: 0.00805 AC: 360 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0158 AC: 412 AN: 26126

East Asian (EAS) AF: 0.145 AC: 5749 AN: 39644

South Asian (SAS) AF: 0.0146 AC: 1262 AN: 86246

European-Finnish (FIN) AF: 0.0251 AC: 1342 AN: 53406

Middle Eastern (MID) AF: 0.0170 AC: 98 AN: 5762

European-Non Finnish (NFE) AF: 0.00165 AC: 1840 AN: 1111828

Other (OTH) AF: 0.0194 AC: 1170 AN: 60346

GnomAD4 genome AF: 0.0293 AC: 4465 AN: 152216 Hom.: 164 Cov.: 32 AF XY: 0.0306 AC XY: 2276 AN XY: 74440

African (AFR) AF: 0.0673 AC: 2793 AN: 41526

American (AMR) AF: 0.0152 AC: 233 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00922 AC: 32 AN: 3472

East Asian (EAS) AF: 0.143 AC: 740 AN: 5172

South Asian (SAS) AF: 0.0249 AC: 120 AN: 4826

European-Finnish (FIN) AF: 0.0271 AC: 287 AN: 10600

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.00296 AC: 201 AN: 68016

Other (OTH) AF: 0.0232 AC: 49 AN: 2108

Alfa AF: 0.0131 Hom.: 284

Bravo AF: 0.0312

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.0666 AC: 253

ESP6500EA AF: 0.00243 AC: 20

ExAC AF: 0.0234 AC: 2822

Asia WGS AF: 0.0960 AC: 332 AN: 3478

EpiCase AF: 0.00316

EpiControl AF: 0.00373

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	5	not specified (5)
-	-	2	Alport syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	0.019
DANN	Benign	0.70
DEOGEN2	Benign	0.18	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.4	L
PhyloP100		-1.3
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.33
Sift	Benign	0.92	T
Sift4G	Benign	0.85	T
Polyphen		0.75	P
Vest4		0.081
MPC		0.24
ClinPred		0.0082	T
GERP RS		-5.1
Varity_R		0.048
gMVP		0.43
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.030		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: rs80109666; hg19: chr2-228118867; COSMIC: COSV67414559;