X-108440156-G-T

Variant names:

• chrX-108440156-G-T
• rs370313574
• NM_033380.3:c.31G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_033380.3(COL4A5):​c.31G>T​(p.Gly11Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000912 in 1,097,069 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). 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: 9.1e-7 (0 hom. 0 hem.)
• Consequence: COL4A5 NM_033380.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.85

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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). GenCC associations: The gene is linked to X-linked Alport syndrome, Alport syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.20523033).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A5	NM_033380.3	c.31G>T	p.Gly11Cys	missense_variant	Exon 1 of 53	ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11	c.31G>T	p.Gly11Cys	missense_variant	Exon 1 of 53	1	NM_033380.3	ENSP00000331902.7

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome AF: 9.12e-7 AC: 1 AN: 1097069 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 362471

African (AFR) AF: 0.00 AC: 0 AN: 26383

American (AMR) AF: 0.00 AC: 0 AN: 35192

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19374

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30203

South Asian (SAS) AF: 0.00 AC: 0 AN: 54043

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40267

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4089

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841479

Other (OTH) AF: 0.00 AC: 0 AN: 46039

GnomAD4 genome Cov.: 20

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked Alport syndrome Uncertain:1

Apr 15, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	0.0016	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.091	.;T
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.57	T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	0.0	N;N
PhyloP100		1.8
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.65	N;N
REVEL	Benign	0.23
Sift	Benign	0.20	T;T
Sift4G	Benign	0.21	T;T
Polyphen		0.041	.;B
Vest4		0.39
MutPred		0.62		Loss of MoRF binding (P = 0.0755);Loss of MoRF binding (P = 0.0755);
MVP		0.64
MPC		0.32
ClinPred		0.23	T
GERP RS		2.9
PromoterAI		-0.0056	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.87
Mutation Taster		=82/18	polymorphism

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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Other links and lift over

dbSNP: rs370313574; hg19: chrX-107683386;