dbSNP rs147085074: COL4A3:p.Gly1086Gly (chr2-227293238-G-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_000091.5(COL4A3):c.3258G>A(p.Gly1086Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00472 in 1,613,918 control chromosomes in the GnomAD database, including 39 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 0.0038 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0048 ( 37 hom. )

Consequence

COL4A3
NM_000091.5 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:12

Conservation

PhyloP100: -0.953

Publications

0 publications found

Variant links:

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]

COL4A3 links:

MFF-DT (HGNC:41067): (MFF divergent transcript)

MFF-DT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 2-227293238-G-A is Benign according to our data. Variant chr2-227293238-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 254991.

BP7

Synonymous conserved (PhyloP=-0.953 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00385 (586/152286) while in subpopulation AMR AF = 0.00654 (100/15300). AF 95% confidence interval is 0.0055. There are 2 homozygotes in GnomAd4. There are 304 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR,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.3258G>A	p.Gly1086Gly	synonymous	Exon 38 of 52	NP_000082.2	Q01955-1
	MFF-DT	NR_102371.1		n.244-11449C>T		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COL4A3	ENST00000396578.8	TSL:1 MANE Select	c.3258G>A	p.Gly1086Gly	synonymous	Exon 38 of 52	ENSP00000379823.3	Q01955-1
MFF-DT	ENST00000439598.6	TSL:1	n.244-11449C>T		intron	N/A
COL4A3	ENST00000871618.1		c.3258G>A	p.Gly1086Gly	synonymous	Exon 38 of 52	ENSP00000541677.1

Frequencies

GnomAD3 genomes

AF:

0.00385

AC:

586

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000821

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00654

Gnomad ASJ

AF:

0.0302

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00249

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00463

Gnomad OTH

AF:

0.00574

GnomAD2 exomes

AF:

0.00444

AC:

1109

AN:

249512

AF XY:

0.00454

show subpopulations

Gnomad AFR exome

AF:

0.000710

Gnomad AMR exome

AF:

0.00229

Gnomad ASJ exome

AF:

0.0309

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000325

Gnomad NFE exome

AF:

0.00449

Gnomad OTH exome

AF:

0.00726

GnomAD4 exome

AF:

0.00481

AC:

7026

AN:

1461632

Hom.:

Cov.:

AF XY:

0.00478

AC XY:

3476

AN XY:

727118

show subpopulations

African (AFR)

AF:

0.00111

AC:

AN:

33476

American (AMR)

AF:

0.00257

AC:

115

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0300

AC:

784

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00471

AC:

406

AN:

86242

European-Finnish (FIN)

AF:

0.000524

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.0199

AC:

111

AN:

5584

European-Non Finnish (NFE)

AF:

0.00461

AC:

5121

AN:

1111992

Other (OTH)

AF:

0.00701

AC:

423

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

373

746

1118

1491

1864

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

212

424

636

848

1060

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00385

AC:

586

AN:

152286

Hom.:

Cov.:

AF XY:

0.00408

AC XY:

304

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.000818

AC:

AN:

41560

American (AMR)

AF:

0.00654

AC:

100

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0302

AC:

105

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00249

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00463

AC:

315

AN:

68028

Other (OTH)

AF:

0.00568

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

100

134

167

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00619

Hom.:

Bravo

AF:

0.00437

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.00562

EpiControl

AF:

0.00557

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

not specified (3)

Alport syndrome (2)

Autosomal recessive Alport syndrome (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

4.8

(source)

DANN

Benign

0.70

PhyloP100

-0.95

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over