X-108626251-C-T

Position:

chrX-108626251-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_033380.3(COL4A5):c.3148C>T(p.Pro1050Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000238 in 1,208,151 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 82 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1050A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., 44 hem., cov: 22)

Exomes 𝑓: 0.00012 ( 0 hom. 38 hem. )

Consequence

COL4A5
NM_033380.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 3.51

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a compositionally_biased_region Pro residues (size 14) in uniprot entity CO4A5_HUMAN there are 8 pathogenic changes around while only 2 benign (80%) in NM_033380.3

BP4

Computational evidence support a benign effect (MetaRNN=0.023664653).

BP6

Variant X-108626251-C-T is Benign according to our data. Variant chrX-108626251-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 446016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00138 (154/111400) while in subpopulation AFR AF= 0.00472 (145/30699). AF 95% confidence interval is 0.0041. There are 0 homozygotes in gnomad4. There are 44 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 44 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A5	NM_033380.3 linkuse as main transcript	c.3148C>T	p.Pro1050Ser	missense_variant	36/53	ENST00000328300.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A5	ENST00000328300.11 linkuse as main transcript	c.3148C>T	p.Pro1050Ser	missense_variant	36/53	1	NM_033380.3		P29400-2
COL4A5	ENST00000483338.1 linkuse as main transcript	c.1972C>T	p.Pro658Ser	missense_variant	20/20	1
COL4A5	ENST00000361603.7 linkuse as main transcript	c.3148C>T	p.Pro1050Ser	missense_variant	36/51	2		P1	P29400-1
COL4A5	ENST00000505728.1 linkuse as main transcript	c.382C>T	p.Pro128Ser	missense_variant	4/5	3

Frequencies

GnomAD3 genomes

AF:

0.00138

AC:

154

AN:

111348

Hom.:

Cov.:

AF XY:

0.00131

AC XY:

AN XY:

33530

show subpopulations

Gnomad AFR

AF:

0.00473

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000574

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:

0.0000189

Gnomad OTH

AF:

0.00134

GnomAD3 exomes

AF:

0.000377

AC:

AN:

183192

Hom.:

AF XY:

0.000310

AC XY:

AN XY:

67732

show subpopulations

Gnomad AFR exome

AF:

0.00471

Gnomad AMR exome

AF:

0.000219

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:

0.00

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.000122

AC:

134

AN:

1096751

Hom.:

Cov.:

AF XY:

0.000105

AC XY:

AN XY:

362365

show subpopulations

Gnomad4 AFR exome

AF:

0.00429

Gnomad4 AMR exome

AF:

0.000284

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:

0.00

Gnomad4 OTH exome

AF:

0.000239

GnomAD4 genome

AF:

0.00138

AC:

154

AN:

111400

Hom.:

Cov.:

AF XY:

0.00131

AC XY:

AN XY:

33592

show subpopulations

Gnomad4 AFR

AF:

0.00472

Gnomad4 AMR

AF:

0.000574

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000189

Gnomad4 OTH

AF:

0.00133

Alfa

AF:

0.000138

Hom.:

Bravo

AF:

0.00147

ESP6500AA

AF:

0.00261

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000404

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 10, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 28, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 28, 2018	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Sep 19, 2017

- -

COL4A5-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 05, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

X-linked Alport syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 29, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.17

CADD

Benign

DANN

Uncertain

1.0

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.024

T;T;T

MetaSVM

Uncertain

0.29

MutationAssessor

Uncertain

2.2

M;M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-3.2

D;D;.

REVEL

Uncertain

0.40

Sift

Uncertain

0.012

D;D;.

Sift4G

Benign

0.15

T;T;.

Polyphen

0.14

.;B;B

Vest4

0.35

MVP

0.85

MPC

0.30

ClinPred

0.037

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.33

gMVP

0.39

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