chrX-108440171-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_033380.3(COL4A5):​c.46G>C​(p.Ala16Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 21)

Consequence

COL4A5
NM_033380.3 missense

Scores

3
5
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.71
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.899

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
COL4A5NM_033380.3 linkuse as main transcriptc.46G>C p.Ala16Pro missense_variant 1/53 ENST00000328300.11 NP_203699.1
COL4A5NM_000495.5 linkuse as main transcriptc.46G>C p.Ala16Pro missense_variant 1/51 NP_000486.1
COL4A5XM_047441811.1 linkuse as main transcriptc.46G>C p.Ala16Pro missense_variant 1/42 XP_047297767.1
COL4A5XM_047441810.1 linkuse as main transcriptc.-331G>C 5_prime_UTR_variant 1/54 XP_047297766.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
COL4A5ENST00000328300.11 linkuse as main transcriptc.46G>C p.Ala16Pro missense_variant 1/531 NM_033380.3 ENSP00000331902 P29400-2

Frequencies

GnomAD3 genomes
Cov.:
21
GnomAD4 exome
Cov.:
29
GnomAD4 genome
Cov.:
21

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 11, 2021The c.46G>C (p.A16P) alteration is located in exon 1 (coding exon 1) of the COL4A5 gene. This alteration results from a G to C substitution at nucleotide position 46, causing the alanine (A) at amino acid position 16 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.24
BayesDel_addAF
Pathogenic
0.23
D
BayesDel_noAF
Uncertain
0.090
CADD
Benign
21
DANN
Uncertain
0.99
DEOGEN2
Benign
0.14
.;T
FATHMM_MKL
Benign
0.68
D
LIST_S2
Benign
0.66
T;T
M_CAP
Pathogenic
0.44
D
MetaRNN
Pathogenic
0.90
D;D
MetaSVM
Uncertain
0.53
D
MutationAssessor
Benign
0.0
N;N
MutationTaster
Benign
0.70
D;D
PrimateAI
Uncertain
0.56
T
PROVEAN
Benign
-0.92
N;N
REVEL
Uncertain
0.49
Sift
Benign
0.20
T;T
Sift4G
Benign
0.11
T;T
Polyphen
1.0
.;D
Vest4
0.73
MutPred
0.73
Loss of helix (P = 0.0033);Loss of helix (P = 0.0033);
MVP
0.96
MPC
0.39
ClinPred
0.71
D
GERP RS
4.7
Varity_R
0.53
gMVP
0.51

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-107683401; API