NM_033380.3:c.32G>T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP2BP4BS2

The NM_033380.3(COL4A5):c.32G>T(p.Gly11Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000125 in 1,205,867 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 47 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G11C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000083 ( 0 hom., 3 hem., cov: 21)

Exomes 𝑓: 0.00013 ( 0 hom. 44 hem. )

Consequence

COL4A5
NM_033380.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.69

Publications

0 publications found

Variant links:

Genes affected

COL4A5 (HGNC:2207): (collagen type IV alpha 5 chain) This gene encodes one of the six subunits of type IV collagen, the major structural component of basement membranes. Mutations in this gene are associated with X-linked Alport syndrome, also known as hereditary nephritis. 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. Alternatively spliced transcript variants have been identified for this gene. [provided by RefSeq, Aug 2010]

COL4A5 Gene-Disease associations (from GenCC):

Alport syndrome
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen, G2P
X-linked Alport syndrome
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Genomics England PanelApp, Myriad Women’s Health, Orphanet, Labcorp Genetics (formerly Invitae)

COL4A5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 538 curated pathogenic missense variants (we use a threshold of 10). The gene has 138 curated benign missense variants. Gene score misZ: 2.4995 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to X-linked Alport syndrome, Alport syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.38764292).

BS2

High Hemizygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A5	NM_033380.3 link	c.32G>T	p.Gly11Val	missense_variant	Exon 1 of 53	ENST00000328300.11	NP_203699.1	P29400-2Q49AM6A7MBN3
COL4A5	NM_000495.5 link	c.32G>T	p.Gly11Val	missense_variant	Exon 1 of 51		NP_000486.1	P29400-1Q49AM6A7MBN3
COL4A5	XM_047441811.1 link	c.32G>T	p.Gly11Val	missense_variant	Exon 1 of 42		XP_047297767.1
COL4A5	XM_047441810.1 link	c.-345G>T		5_prime_UTR_variant	Exon 1 of 54		XP_047297766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11 link	c.32G>T	p.Gly11Val	missense_variant	Exon 1 of 53	1	NM_033380.3	ENSP00000331902.7		P29400-2

Frequencies

GnomAD3 genomes

AF:

0.0000826

AC:

AN:

108996

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000671

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000987

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000114

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000771

AC:

AN:

181467

AF XY:

0.0000604

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000110

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000136

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000129

AC:

142

AN:

1096871

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

362303

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26384

American (AMR)

AF:

0.0000852

AC:

AN:

35196

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19372

East Asian (EAS)

AF:

0.00

AC:

AN:

30200

South Asian (SAS)

AF:

0.00

AC:

AN:

54030

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40217

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4080

European-Non Finnish (NFE)

AF:

0.000164

AC:

138

AN:

841364

Other (OTH)

AF:

0.0000217

AC:

AN:

46028

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000826

AC:

AN:

108996

Hom.:

Cov.:

AF XY:

0.0000959

AC XY:

AN XY:

31270

show subpopulations

African (AFR)

AF:

0.0000671

AC:

AN:

29823

American (AMR)

AF:

0.0000987

AC:

AN:

10136

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2608

East Asian (EAS)

AF:

0.00

AC:

AN:

3437

South Asian (SAS)

AF:

0.00

AC:

AN:

2430

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5638

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.000114

AC:

AN:

52571

Other (OTH)

AF:

0.00

AC:

AN:

1443

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.533

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.0000718

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000595

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Jan 24, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.32G>T (p.G11V) alteration is located in exon 1 (coding exon 1) of the COL4A5 gene. This alteration results from a G to T substitution at nucleotide position 32, causing the glycine (G) at amino acid position 11 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.049

BayesDel_addAF

Benign

-0.043

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.091

.;T

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.72

T;T

M_CAP

Pathogenic

0.53

MetaRNN

Benign

0.39

T;T

MetaSVM

Uncertain

-0.27

MutationAssessor

Benign

0.0

N;N

PhyloP100

2.7

PrimateAI

Uncertain

0.54

PROVEAN

Benign

0.59

N;N

REVEL

Uncertain

0.51

Sift

Benign

0.55

T;T

Sift4G

Benign

0.59

T;T

Polyphen

0.80

.;P

Vest4

0.45

MutPred

0.47

Loss of MoRF binding (P = 0.1336);Loss of MoRF binding (P = 0.1336);

MVP

0.94

MPC

0.37

ClinPred

0.074

GERP RS

4.7

PromoterAI

0.082

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.30

gMVP

0.72

Mutation Taster

=96/4

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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NM_033380.3:c.32G>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over