X-108601950-A-G

Variant names:

• chrX-108601950-A-G
• rs104886155
• NM_033380.3:c.2107A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 5P and 3B. PM1 PM2 PP2 BP4 BP6_Moderate

The NM_033380.3(COL4A5):​c.2107A>G​(p.Ile703Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000381 in 1,050,529 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. I703I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000038 (0 hom. 1 hem.)
• Consequence: COL4A5 NM_033380.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.582
• Publications: 3 publications found

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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_033380.3
• 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). Trascript score misZ: NaN (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=0.3057886).
• BP6: Variant X-108601950-A-G is Benign according to our data. Variant chrX-108601950-A-G is described in ClinVar as Benign. ClinVar VariationId is 24486.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A5	NM_033380.3	c.2107A>G	p.Ile703Val	missense_variant	Exon 27 of 53	ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11	c.2107A>G	p.Ile703Val	missense_variant	Exon 27 of 53	1	NM_033380.3	ENSP00000331902.7
COL4A5	ENST00000483338.1	c.931A>G	p.Ile311Val	missense_variant	Exon 11 of 20	1		ENSP00000495685.1
COL4A5	ENST00000361603.7	c.2107A>G	p.Ile703Val	missense_variant	Exon 27 of 51	2		ENSP00000354505.2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.0000154 AC: 2 AN: 129931 AF XY: 0.0000242

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000198

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000381 AC: 4 AN: 1050529 Hom.: 0 Cov.: 26 AF XY: 0.00000301 AC XY: 1 AN XY: 332401

African (AFR) AF: 0.00 AC: 0 AN: 25432

American (AMR) AF: 0.00 AC: 0 AN: 29931

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18620

East Asian (EAS) AF: 0.000141 AC: 4 AN: 28457

South Asian (SAS) AF: 0.00 AC: 0 AN: 50301

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38322

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4032

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 811141

Other (OTH) AF: 0.00 AC: 0 AN: 44293

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked Alport syndrome Benign:1

May 28, 2019

Mendelics

Significance: Benign

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	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	12
DANN	Benign	0.86
DEOGEN2	Benign	0.31	.;T;T
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.60	T;T;T
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.31	T;T;T
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	0.73	N;N;.
PhyloP100		0.58
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.020	N;N;.
REVEL	Uncertain	0.53
Sift	Benign	0.92	T;T;.
Sift4G	Benign	0.55	T;T;.
Polyphen		0.0090, 0.0030	.;B;B
Vest4		0.16
MutPred		0.74		Loss of sheet (P = 0.1907);Loss of sheet (P = 0.1907);.;
MVP		0.98
MPC		0.25
ClinPred		0.030	T
GERP RS		4.3
Varity_R		0.099
gMVP		0.31
Mutation Taster		=98/2	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

Other links and lift over

dbSNP: rs104886155; hg19: chrX-107845180;