X-108680694-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_033380.3(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).

Frequency

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

Exomes 𝑓: 0.00013 ( 0 hom. 37 hem. )

Consequence

COL4A5
NM_033380.3 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 -12 ACMG points.

BP4

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

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000153 (17/111031) while in subpopulation EAS AF= 0.00425 (15/3528). AF 95% confidence interval is 0.00262. There are 0 homozygotes in gnomad4. There are 3 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.

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.3958C>T	p.Pro1320Ser	missense_variant	Exon 45 of 53	ENST00000328300.11	NP_203699.1	P29400-2Q49AM6A7MBN3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
COL4A5	ENST00000328300.11 link	c.3958C>T	p.Pro1320Ser	missense_variant	Exon 45 of 53	1	NM_033380.3	ENSP00000331902.7	P29400-2
COL4A5	ENST00000361603.7 link	c.3940C>T	p.Pro1314Ser	missense_variant	Exon 43 of 51	2		ENSP00000354505.2	P29400-1
COL4A5	ENST00000489230.1 link	n.361C>T		non_coding_transcript_exon_variant	Exon 4 of 8	5
COL4A5	ENST00000510690.2 link	n.452C>T		non_coding_transcript_exon_variant	Exon 3 of 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

Mar 28, 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

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