X-108575993-T-C

Variant names:

• chrX-108575993-T-C
• rs6622333
• NM_033380.3:c.609+21T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_033380.3(COL4A5):​c.609+21T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.227 in 1,064,430 control chromosomes in the GnomAD database, including 24,049 homozygotes. There are 72,216 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (2111 hom., 6467 hem., cov: 22)
  • Exomes 𝑓: 0.23 (21938 hom. 65749 hem.)
• Consequence: COL4A5 NM_033380.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.116
• Publications: 9 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, Orphanet, Genomics England PanelApp, Myriad Women’s Health, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant X-108575993-T-C is Benign according to our data. Variant chrX-108575993-T-C is described in ClinVar as Benign. ClinVar VariationId is 24296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.55 is higher than 0.05.

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.609+21T>C		intron	N/A	NP_203699.1	P29400-2
	COL4A5	NM_000495.5		c.609+21T>C		intron	N/A	NP_000486.1	P29400-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A5	ENST00000328300.11	TSL:1 MANE Select	c.609+21T>C		intron	N/A	ENSP00000331902.7	P29400-2
	COL4A5	ENST00000949143.1		c.609+21T>C		intron	N/A	ENSP00000619202.1
	COL4A5	ENST00000361603.7	TSL:2	c.609+21T>C		intron	N/A	ENSP00000354505.2	P29400-1

Frequencies

GnomAD3 genomes AF: 0.196 AC: 21656 AN: 110406 Hom.: 2111 Cov.: 22

Gnomad AFR AF: 0.0638

Gnomad AMI AF: 0.356

Gnomad AMR AF: 0.437

Gnomad ASJ AF: 0.170

Gnomad EAS AF: 0.571

Gnomad SAS AF: 0.370

Gnomad FIN AF: 0.134

Gnomad MID AF: 0.195

Gnomad NFE AF: 0.198

Gnomad OTH AF: 0.218

GnomAD2 exomes AF: 0.300 AC: 45808 AN: 152783 AF XY: 0.295

Gnomad AFR exome AF: 0.0591

Gnomad AMR exome AF: 0.610

Gnomad ASJ exome AF: 0.179

Gnomad EAS exome AF: 0.562

Gnomad FIN exome AF: 0.141

Gnomad NFE exome AF: 0.198

Gnomad OTH exome AF: 0.270

GnomAD4 exome AF: 0.230 AC: 219441 AN: 953977 Hom.: 21938 Cov.: 18 AF XY: 0.248 AC XY: 65749 AN XY: 265611

African (AFR) AF: 0.0587 AC: 1383 AN: 23554

American (AMR) AF: 0.586 AC: 19901 AN: 33984

Ashkenazi Jewish (ASJ) AF: 0.178 AC: 3266 AN: 18305

East Asian (EAS) AF: 0.640 AC: 18327 AN: 28643

South Asian (SAS) AF: 0.377 AC: 18492 AN: 49091

European-Finnish (FIN) AF: 0.148 AC: 5835 AN: 39342

Middle Eastern (MID) AF: 0.192 AC: 735 AN: 3821

European-Non Finnish (NFE) AF: 0.198 AC: 142059 AN: 716178

Other (OTH) AF: 0.230 AC: 9443 AN: 41059

GnomAD4 genome AF: 0.196 AC: 21666 AN: 110453 Hom.: 2111 Cov.: 22 AF XY: 0.198 AC XY: 6467 AN XY: 32715

African (AFR) AF: 0.0639 AC: 1945 AN: 30459

American (AMR) AF: 0.437 AC: 4489 AN: 10263

Ashkenazi Jewish (ASJ) AF: 0.170 AC: 448 AN: 2640

East Asian (EAS) AF: 0.571 AC: 1981 AN: 3470

South Asian (SAS) AF: 0.372 AC: 952 AN: 2562

European-Finnish (FIN) AF: 0.134 AC: 778 AN: 5817

Middle Eastern (MID) AF: 0.200 AC: 43 AN: 215

European-Non Finnish (NFE) AF: 0.198 AC: 10471 AN: 52860

Other (OTH) AF: 0.214 AC: 321 AN: 1498

Alfa AF: 0.176 Hom.: 3959

Bravo AF: 0.218

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	X-linked Alport syndrome (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	2.4
DANN	Benign	0.83
PhyloP100		0.12
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs6622333; hg19: chrX-107819223;