chrX-108440156-G-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP2PP3BS2

The NM_033380.3(COL4A5):c.31G>C(p.Gly11Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000638 in 1,097,069 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G11V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 20)

Exomes 𝑓: 0.0000064 ( 0 hom. 5 hem. )

Consequence

COL4A5
NM_033380.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.85

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.778

BS2

High Hemizygotes in GnomAdExome4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A5	NM_033380.3 link	c.31G>C	p.Gly11Arg	missense_variant	Exon 1 of 53	ENST00000328300.11	NP_203699.1	P29400-2Q49AM6A7MBN3
COL4A5	NM_000495.5 link	c.31G>C	p.Gly11Arg	missense_variant	Exon 1 of 51		NP_000486.1	P29400-1Q49AM6A7MBN3
COL4A5	XM_047441811.1 link	c.31G>C	p.Gly11Arg	missense_variant	Exon 1 of 42		XP_047297767.1
COL4A5	XM_047441810.1 link	c.-346G>C		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.31G>C	p.Gly11Arg	missense_variant	Exon 1 of 53	1	NM_033380.3	ENSP00000331902.7		P29400-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000638

AC:

AN:

1097069

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

362471

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26383

American (AMR)

AF:

0.00

AC:

AN:

35192

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19374

East Asian (EAS)

AF:

0.00

AC:

AN:

30203

South Asian (SAS)

AF:

0.00

AC:

AN:

54043

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40267

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4089

European-Non Finnish (NFE)

AF:

0.00000832

AC:

AN:

841479

Other (OTH)

AF:

0.00

AC:

AN:

46039

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.12

.;T

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.77

T;T

M_CAP

Benign

0.043

MetaRNN

Pathogenic

0.78

D;D

MetaSVM

Benign

-0.34

MutationAssessor

Benign

0.0

N;N

PhyloP100

1.8

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.60

N;N

REVEL

Uncertain

0.48

Sift

Benign

0.40

T;T

Sift4G

Benign

0.41

T;T

Polyphen

0.99

.;D

Vest4

0.68

MutPred

0.72

Gain of MoRF binding (P = 8e-04);Gain of MoRF binding (P = 8e-04);

MVP

0.92

MPC

0.36

ClinPred

0.44

GERP RS

2.9

PromoterAI

-0.14

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.097

gMVP

0.80

Mutation Taster

=79/21

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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chrX-108440156-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over