Genetic Variant COL4A4:c.2716+142C>G (chr2-227055803-G-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000092.5(COL4A4):c.2716+142C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00286 in 742,898 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0092 ( 21 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 9 hom. )

Consequence

COL4A4
NM_000092.5 intron

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.217

Variant links:

Genes affected

COL4A4 (HGNC:2206): (collagen type IV alpha 4 chain) This gene encodes one of the six subunits of type IV collagen, the major structural component of basement membranes. This particular collagen IV subunit, however, is only found in a subset of basement membranes. 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. Mutations in this gene are associated with type II autosomal recessive Alport syndrome (hereditary glomerulonephropathy) and with familial benign hematuria (thin basement membrane disease). Two transcripts, differing only in their transcription start sites, have been identified for this gene and, as is common for collagen genes, multiple polyadenylation sites are found in the 3' UTR. [provided by RefSeq, Jul 2008]

COL4A4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 2-227055803-G-C is Benign according to our data. Variant chr2-227055803-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 1214289.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227055803-G-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00919 (1400/152272) while in subpopulation AFR AF = 0.0317 (1316/41540). AF 95% confidence interval is 0.0303. There are 21 homozygotes in GnomAd4. There are 682 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.

BS2

High Homozygotes in GnomAd4 at 21 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A4	NM_000092.5 link	c.2716+142C>G		intron_variant	Intron 30 of 47	ENST00000396625.5	NP_000083.3	P53420

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A4	ENST00000396625.5 link	c.2716+142C>G		intron_variant	Intron 30 of 47	5	NM_000092.5	ENSP00000379866.3		P53420

Frequencies

GnomAD3 genomes

AF:

0.00919

AC:

1399

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0317

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00294

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.00907

GnomAD4 exome

AF:

0.00122

AC:

722

AN:

590626

Hom.:

AF XY:

0.00109

AC XY:

342

AN XY:

312494

show subpopulations

African (AFR)

AF:

0.0301

AC:

466

AN:

15496

American (AMR)

AF:

0.00192

AC:

AN:

24446

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15026

East Asian (EAS)

AF:

0.00

AC:

AN:

34966

South Asian (SAS)

AF:

0.0000951

AC:

AN:

52592

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42776

Middle Eastern (MID)

AF:

0.00860

AC:

AN:

3604

European-Non Finnish (NFE)

AF:

0.000232

AC:

AN:

370456

Other (OTH)

AF:

0.00278

AC:

AN:

31264

Heterozygous variant carriers

106

141

176

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00919

AC:

1400

AN:

152272

Hom.:

Cov.:

AF XY:

0.00916

AC XY:

682

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.0317

AC:

1316

AN:

41540

American (AMR)

AF:

0.00294

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000279

AC:

AN:

68018

Other (OTH)

AF:

0.00898

AC:

AN:

2116

Heterozygous variant carriers

146

218

291

364

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

100

<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:

0.000107

Hom.:

Bravo

AF:

0.0101

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jul 10, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

4.3

DANN

Benign

0.36

Mutation Taster

=100/0

polymorphism

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over