rs104886399

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4BS2

The NM_033380.3(COL4A5):c.3923A>G(p.Gln1308Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,209,134 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 13 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000054 ( 0 hom., 3 hem., cov: 24)

Exomes 𝑓: 0.000022 ( 0 hom. 10 hem. )

Consequence

COL4A5
NM_033380.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.19

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 1 uncertain in NM_033380.3

BP4

Computational evidence support a benign effect (MetaRNN=0.3822859).

BS2

High Hemizygotes in GnomAd at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A5	NM_033380.3 linkuse as main transcript	c.3923A>G	p.Gln1308Arg	missense_variant	44/53	ENST00000328300.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A5	ENST00000328300.11 linkuse as main transcript	c.3923A>G	p.Gln1308Arg	missense_variant	44/53	1	NM_033380.3		P29400-2
COL4A5	ENST00000361603.7 linkuse as main transcript	c.3905A>G	p.Gln1302Arg	missense_variant	42/51	2		P1	P29400-1
COL4A5	ENST00000489230.1 linkuse as main transcript	n.326A>G		non_coding_transcript_exon_variant	3/8	5
COL4A5	ENST00000510690.2 linkuse as main transcript	n.417A>G		non_coding_transcript_exon_variant	2/11	4

Frequencies

GnomAD3 genomes

AF:

0.0000535

AC:

AN:

112080

Hom.:

Cov.:

AF XY:

0.0000876

AC XY:

AN XY:

34238

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000948

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000562

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000564

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000383

AC:

AN:

182905

Hom.:

AF XY:

0.0000593

AC XY:

AN XY:

67501

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000732

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000613

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000219

AC:

AN:

1097054

Hom.:

Cov.:

AF XY:

0.0000276

AC XY:

AN XY:

362700

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000854

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000202

Gnomad4 OTH exome

AF:

0.0000652

GnomAD4 genome

AF:

0.0000535

AC:

AN:

112080

Hom.:

Cov.:

AF XY:

0.0000876

AC XY:

AN XY:

34238

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000948

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000562

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000564

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000680

Hom.:

Bravo

AF:

0.000106

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.000238

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 17, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 03, 2023	- -

X-linked Alport syndrome

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Feb 27, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.38

Cadd

Benign

Dann

Benign

0.86

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.79

T;T

M_CAP

Pathogenic

0.31

MetaRNN

Benign

0.38

T;T

MetaSVM

Uncertain

-0.22

MutationTaster

Benign

0.95

N;N

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.78

N;N

REVEL

Uncertain

0.48

Sift

Benign

0.48

T;T

Sift4G

Benign

0.55

T;T

Polyphen

0.64

.;P

Vest4

0.31

MutPred

0.37

.;Gain of methylation at Q1302 (P = 0.0168);

MVP

1.0

MPC

0.32

ClinPred

0.15

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.52

gMVP

0.29

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