X-108680941-C-G

Variant names:

• chrX-108680941-C-G
• NM_033380.3:c.4072C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_033380.3(COL4A5):​c.4072C>G​(p.Leu1358Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000915 in 1,093,356 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign 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. L1358I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: COL4A5 NM_033380.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.838

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 3 uncertain in NM_033380.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16583315).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A5	NM_033380.3	c.4072C>G	p.Leu1358Val	missense_variant	Exon 46 of 53	ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11	c.4072C>G	p.Leu1358Val	missense_variant	Exon 46 of 53	1	NM_033380.3	ENSP00000331902.7
COL4A5	ENST00000361603.7	c.4054C>G	p.Leu1352Val	missense_variant	Exon 44 of 51	2		ENSP00000354505.2
COL4A5	ENST00000489230.1	n.475C>G		non_coding_transcript_exon_variant	Exon 5 of 8	5
COL4A5	ENST00000510690.2	n.566C>G		non_coding_transcript_exon_variant	Exon 4 of 11	4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.15e-7 AC: 1 AN: 1093356 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 358928

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	14
DANN	Benign	0.94
DEOGEN2	Benign	0.11	.;T
FATHMM_MKL	Benign	0.13	N
LIST_S2	Uncertain	0.90	D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	0.94	.;L
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.22	N;N
REVEL	Uncertain	0.40
Sift	Benign	0.61	T;T
Sift4G	Benign	0.68	T;T
Polyphen		0.023	.;B
Vest4		0.12
MutPred		0.34		.;Loss of glycosylation at P1356 (P = 0.2061);
MVP		0.92
MPC		0.32
ClinPred		0.17	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.15
gMVP		0.078

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-107924171;