X-108680694-C-T

Position:

chrX-108680694-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM1BP4_StrongBS1BS2

The ENST00000328300.11(COL4A5):c.3958C>T(p.Pro1320Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000129 in 1,207,663 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 40 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1320L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., 3 hem., cov: 22)

Exomes 𝑓: 0.00013 ( 0 hom. 37 hem. )

Consequence

COL4A5
ENST00000328300.11 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 3.57

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 Benign. Variant got -10 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in ENST00000328300.11

BP4

Computational evidence support a benign effect (MetaRNN=0.03224808).

BS1

Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.000127 (139/1096632) while in subpopulation EAS AF= 0.00408 (123/30177). AF 95% confidence interval is 0.00349. There are 0 homozygotes in gnomad4_exome. There are 37 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A5	NM_033380.3 linkuse as main transcript	c.3958C>T	p.Pro1320Ser	missense_variant	45/53	ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11 linkuse as main transcript	c.3958C>T	p.Pro1320Ser	missense_variant	45/53	1	NM_033380.3	ENSP00000331902		P29400-2
COL4A5	ENST00000361603.7 linkuse as main transcript	c.3940C>T	p.Pro1314Ser	missense_variant	43/51	2		ENSP00000354505	P1	P29400-1
COL4A5	ENST00000489230.1 linkuse as main transcript	n.361C>T		non_coding_transcript_exon_variant	4/8	5
COL4A5	ENST00000510690.2 linkuse as main transcript	n.452C>T		non_coding_transcript_exon_variant	3/11	4

Frequencies

GnomAD3 genomes

AF:

0.000153

AC:

AN:

110981

Hom.:

Cov.:

AF XY:

0.0000903

AC XY:

AN XY:

33205

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00424

Gnomad SAS

AF:

0.000383

Gnomad FIN

AF:

0.000169

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000323

AC:

AN:

182928

Hom.:

AF XY:

0.000178

AC XY:

AN XY:

67582

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00420

Gnomad SAS exome

AF:

0.0000525

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000127

AC:

139

AN:

1096632

Hom.:

Cov.:

AF XY:

0.000102

AC XY:

AN XY:

362204

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00408

Gnomad4 SAS exome

AF:

0.0000370

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000119

Gnomad4 OTH exome

AF:

0.0000869

GnomAD4 genome

AF:

0.000153

AC:

AN:

111031

Hom.:

Cov.:

AF XY:

0.0000902

AC XY:

AN XY:

33265

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00425

Gnomad4 SAS

AF:

0.000384

Gnomad4 FIN

AF:

0.000169

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000234

ExAC

AF:

0.000288

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Mar 06, 2017

- -

X-linked Alport syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Precision Medicine Center, Zhengzhou University

PM1:Located in a mutational hot spot PP3:Multiple lines of computational evidence support a deleterious effect on the gene or gene product -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.42

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.59

.;D

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.90

D;D

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.032

T;T

MetaSVM

Uncertain

0.61

MutationAssessor

Benign

1.9

.;L

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-3.6

D;D

REVEL

Pathogenic

0.81

Sift

Benign

0.088

T;D

Sift4G

Benign

0.12

T;T

Polyphen

0.61

.;P

Vest4

0.18

MutPred

0.78

.;Gain of relative solvent accessibility (P = 0.0082);

MVP

1.0

MPC

0.85

ClinPred

0.16

GERP RS

4.4

Varity_R

0.31

gMVP

0.40

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