rs73996414

Variant names:

• chr2-227304032-C-A
• rs73996414
• NM_000091.5:c.4041C>A

Your query was ambiguous. Multiple possible variants found:

• chr2-227304032-C-A
• chr2-227304032-C-T

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.4041C>A​(p.Asp1347Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00459 in 1,614,098 control chromosomes in the GnomAD database, including 256 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (146 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (110 hom.)
• Consequence: COL4A3 NM_000091.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -2.27
• Publications: 7 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 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 8 uncertain in NM_000091.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.0026836097).
• BP6: Variant 2-227304032-C-A is Benign according to our data. Variant chr2-227304032-C-A is described in ClinVar as Benign. ClinVar VariationId is 334780.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0793 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.4041C>A	p.Asp1347Glu	missense	Exon 46 of 52	NP_000082.2
	MFF-DT	NR_102371.1		n.243+1428G>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.4041C>A	p.Asp1347Glu	missense	Exon 46 of 52	ENSP00000379823.3
	COL4A3	ENST00000469504.2	TSL:1	n.12C>A		non_coding_transcript_exon	Exon 1 of 6	ENSP00000493493.1
	MFF-DT	ENST00000439598.6	TSL:1	n.243+1428G>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0235 AC: 3579 AN: 152162 Hom.: 146 Cov.: 32

Gnomad AFR AF: 0.0817

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00746

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.0182

GnomAD2 exomes AF: 0.00640 AC: 1596 AN: 249314 AF XY: 0.00489

Gnomad AFR exome AF: 0.0837

Gnomad AMR exome AF: 0.00418

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00234

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000460

Gnomad OTH exome AF: 0.00264

GnomAD4 exome AF: 0.00262 AC: 3831 AN: 1461818 Hom.: 110 Cov.: 31 AF XY: 0.00230 AC XY: 1676 AN XY: 727210

African (AFR) AF: 0.0814 AC: 2723 AN: 33472

American (AMR) AF: 0.00459 AC: 205 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00134 AC: 35 AN: 26136

East Asian (EAS) AF: 0.00123 AC: 49 AN: 39700

South Asian (SAS) AF: 0.00128 AC: 110 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00607 AC: 35 AN: 5768

European-Non Finnish (NFE) AF: 0.000313 AC: 348 AN: 1111984

Other (OTH) AF: 0.00540 AC: 326 AN: 60394

GnomAD4 genome AF: 0.0235 AC: 3584 AN: 152280 Hom.: 146 Cov.: 32 AF XY: 0.0225 AC XY: 1678 AN XY: 74460

African (AFR) AF: 0.0816 AC: 3390 AN: 41552

American (AMR) AF: 0.00745 AC: 114 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3472

East Asian (EAS) AF: 0.00231 AC: 12 AN: 5184

South Asian (SAS) AF: 0.00125 AC: 6 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68016

Other (OTH) AF: 0.0180 AC: 38 AN: 2110

Alfa AF: 0.00931 Hom.: 119

Bravo AF: 0.0276

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.0827 AC: 330

ESP6500EA AF: 0.000240 AC: 2

ExAC AF: 0.00776 AC: 938

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.00107

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	1	Alport syndrome (1)
-	-	1	Atypical hemolytic-uremic syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	6.1
DANN	Benign	0.89
DEOGEN2	Benign	0.24	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.078	N
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	-0.16	N
PhyloP100		-2.3
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.33	N
REVEL	Benign	0.21
Sift	Benign	0.35	T
Sift4G	Benign	1.0	T
Polyphen		0.0020	B
Vest4		0.086
MutPred		0.23		Loss of catalytic residue at G1349 (P = 0.1665)
MVP		0.55
MPC		0.18
ClinPred		0.0031	T
GERP RS		-2.0
Varity_R		0.061
gMVP		0.047
Mutation Taster		=94/6	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: rs73996414; hg19: chr2-228168748;