rs7884085

Variant names:

• chrX-108601898-T-C
• rs7884085
• NM_033380.3:c.2055T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_033380.3(COL4A5):​c.2055T>C​(p.Leu685Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0241 in 1,152,504 control chromosomes in the GnomAD database, including 2,670 homozygotes. There are 7,507 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (1308 hom., 3012 hem., cov: 22)
  • Exomes 𝑓: 0.016 (1362 hom. 4495 hem.)
• Consequence: COL4A5 NM_033380.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.786
• Publications: 7 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: G2P, ClinGen
• X-linked Alport syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, Myriad Women’s Health

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant X-108601898-T-C is Benign according to our data. Variant chrX-108601898-T-C is described in ClinVar as Benign. ClinVar VariationId is 24481.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.786 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.329 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.2055T>C	p.Leu685Leu	synonymous	Exon 27 of 53	NP_203699.1	P29400-2
	COL4A5	NM_000495.5		c.2055T>C	p.Leu685Leu	synonymous	Exon 27 of 51	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.2055T>C	p.Leu685Leu	synonymous	Exon 27 of 53	ENSP00000331902.7	P29400-2
	COL4A5	ENST00000483338.1	TSL:1	c.879T>C	p.Leu293Leu	synonymous	Exon 11 of 20	ENSP00000495685.1	Q49AM6
	COL4A5	ENST00000949143.1		c.2055T>C	p.Leu685Leu	synonymous	Exon 27 of 51	ENSP00000619202.1

Frequencies

GnomAD3 genomes AF: 0.103 AC: 11409 AN: 110806 Hom.: 1308 Cov.: 22

Gnomad AFR AF: 0.334

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0559

Gnomad ASJ AF: 0.00303

Gnomad EAS AF: 0.143

Gnomad SAS AF: 0.0210

Gnomad FIN AF: 0.000166

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00128

Gnomad OTH AF: 0.0889

GnomAD2 exomes AF: 0.0447 AC: 5777 AN: 129141 AF XY: 0.0332

Gnomad AFR exome AF: 0.334

Gnomad AMR exome AF: 0.0427

Gnomad ASJ exome AF: 0.00387

Gnomad EAS exome AF: 0.148

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00104

Gnomad OTH exome AF: 0.0267

GnomAD4 exome AF: 0.0157 AC: 16321 AN: 1041646 Hom.: 1362 Cov.: 25 AF XY: 0.0137 AC XY: 4495 AN XY: 327162

African (AFR) AF: 0.336 AC: 8403 AN: 24977

American (AMR) AF: 0.0466 AC: 1385 AN: 29715

Ashkenazi Jewish (ASJ) AF: 0.00372 AC: 69 AN: 18530

East Asian (EAS) AF: 0.121 AC: 3424 AN: 28376

South Asian (SAS) AF: 0.0145 AC: 724 AN: 50014

European-Finnish (FIN) AF: 0.000183 AC: 7 AN: 38280

Middle Eastern (MID) AF: 0.0116 AC: 46 AN: 3951

European-Non Finnish (NFE) AF: 0.000601 AC: 483 AN: 803842

Other (OTH) AF: 0.0405 AC: 1780 AN: 43961

GnomAD4 genome AF: 0.103 AC: 11420 AN: 110858 Hom.: 1308 Cov.: 22 AF XY: 0.0909 AC XY: 3012 AN XY: 33130

African (AFR) AF: 0.334 AC: 10075 AN: 30150

American (AMR) AF: 0.0557 AC: 587 AN: 10546

Ashkenazi Jewish (ASJ) AF: 0.00303 AC: 8 AN: 2641

East Asian (EAS) AF: 0.142 AC: 494 AN: 3476

South Asian (SAS) AF: 0.0207 AC: 54 AN: 2613

European-Finnish (FIN) AF: 0.000166 AC: 1 AN: 6041

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.00128 AC: 68 AN: 52978

Other (OTH) AF: 0.0878 AC: 133 AN: 1514

Alfa AF: 0.129 Hom.: 1736

Bravo AF: 0.121

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	3	not provided (3)
-	-	2	X-linked Alport syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	6.7
DANN	Benign	0.75
PhyloP100		-0.79
Mutation Taster		=99/1	polymorphism (auto)

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: rs7884085; hg19: chrX-107845128;