rs104886358

Variant names:

• chrX-108620226-A-G
• rs104886358
• NM_033380.3:c.2510-33A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_033380.3(COL4A5):​c.2510-33A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000359 in 1,134,069 control chromosomes in the GnomAD database, including 1 homozygotes. There are 121 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00038 (0 hom., 18 hem., cov: 23)
  • Exomes 𝑓: 0.00036 (1 hom. 103 hem.)
• Consequence: COL4A5 NM_033380.3 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.58
• Publications: 1 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000385 (43/111713) while in subpopulation AMR AF = 0.000668 (7/10474). AF 95% confidence interval is 0.000486. There are 0 homozygotes in GnomAd4. There are 18 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Hemizygotes in GnomAd4 at 18 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033380.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A5	NM_033380.3	MANE Select	c.2510-33A>G		intron	N/A	NP_203699.1
	COL4A5	NM_000495.5		c.2510-33A>G		intron	N/A	NP_000486.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A5	ENST00000328300.11	TSL:1 MANE Select	c.2510-33A>G		intron	N/A	ENSP00000331902.7
	COL4A5	ENST00000483338.1	TSL:1	c.1334-33A>G		intron	N/A	ENSP00000495685.1
	COL4A5	ENST00000949143.1		c.2510-33A>G		intron	N/A	ENSP00000619202.1

Frequencies

GnomAD3 genomes AF: 0.000376 AC: 42 AN: 111661 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000669

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000639

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000284 AC: 51 AN: 179295 AF XY: 0.000273

Gnomad AFR exome AF: 0.0000784

Gnomad AMR exome AF: 0.000146

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000558

Gnomad OTH exome AF: 0.000451

GnomAD4 exome AF: 0.000356 AC: 364 AN: 1022356 Hom.: 1 Cov.: 21 AF XY: 0.000335 AC XY: 103 AN XY: 307020

African (AFR) AF: 0.0000402 AC: 1 AN: 24905

American (AMR) AF: 0.000285 AC: 10 AN: 35081

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18865

East Asian (EAS) AF: 0.00 AC: 0 AN: 29886

South Asian (SAS) AF: 0.0000764 AC: 4 AN: 52323

European-Finnish (FIN) AF: 0.0000248 AC: 1 AN: 40391

Middle Eastern (MID) AF: 0.000654 AC: 2 AN: 3057

European-Non Finnish (NFE) AF: 0.000430 AC: 333 AN: 774307

Other (OTH) AF: 0.000299 AC: 13 AN: 43541

GnomAD4 genome AF: 0.000385 AC: 43 AN: 111713 Hom.: 0 Cov.: 23 AF XY: 0.000531 AC XY: 18 AN XY: 33891

African (AFR) AF: 0.0000325 AC: 1 AN: 30777

American (AMR) AF: 0.000668 AC: 7 AN: 10474

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2648

East Asian (EAS) AF: 0.00 AC: 0 AN: 3540

South Asian (SAS) AF: 0.00 AC: 0 AN: 2652

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6036

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.000658 AC: 35 AN: 53166

Other (OTH) AF: 0.00 AC: 0 AN: 1519

Alfa AF: 0.000924 Hom.: 3

Bravo AF: 0.000408

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	X-linked Alport syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.8
DANN	Benign	0.68
PhyloP100		2.6
Mutation Taster		=100/0	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: rs104886358; hg19: chrX-107863456;