rs61735627

Variant names:

• chrX-108666560-T-G
• rs61735627
• NM_033380.3:c.3519T>G

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.3519T>G​(p.Gly1173Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00577 in 1,206,410 control chromosomes in the GnomAD database, including 242 homozygotes. There are 1,861 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (120 hom., 910 hem., cov: 22)
  • Exomes 𝑓: 0.0033 (122 hom. 951 hem.)
• Consequence: COL4A5 NM_033380.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.151
• Publications: 0 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=-0.47).
• BP6: Variant X-108666560-T-G is Benign according to our data. Variant chrX-108666560-T-G is described in ClinVar as Benign. ClinVar VariationId is 256280.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.151 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.101 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.3519T>G	p.Gly1173Gly	synonymous	Exon 39 of 53	NP_203699.1	P29400-2
	COL4A5	NM_000495.5		c.3519T>G	p.Gly1173Gly	synonymous	Exon 39 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.3519T>G	p.Gly1173Gly	synonymous	Exon 39 of 53	ENSP00000331902.7	P29400-2
	COL4A5	ENST00000949143.1		c.3531T>G	p.Gly1177Gly	synonymous	Exon 39 of 51	ENSP00000619202.1
	COL4A5	ENST00000361603.7	TSL:2	c.3519T>G	p.Gly1173Gly	synonymous	Exon 39 of 51	ENSP00000354505.2	P29400-1

Frequencies

GnomAD3 genomes AF: 0.0300 AC: 3364 AN: 112134 Hom.: 120 Cov.: 22

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0115

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00147

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000300

Gnomad OTH AF: 0.0199

GnomAD2 exomes AF: 0.00888 AC: 1542 AN: 173623 AF XY: 0.00549

Gnomad AFR exome AF: 0.109

Gnomad AMR exome AF: 0.00607

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000248

Gnomad OTH exome AF: 0.00370

GnomAD4 exome AF: 0.00328 AC: 3587 AN: 1094222 Hom.: 122 Cov.: 30 AF XY: 0.00264 AC XY: 951 AN XY: 360102

African (AFR) AF: 0.109 AC: 2872 AN: 26270

American (AMR) AF: 0.00701 AC: 245 AN: 34953

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19323

East Asian (EAS) AF: 0.00 AC: 0 AN: 30049

South Asian (SAS) AF: 0.000281 AC: 15 AN: 53314

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40301

Middle Eastern (MID) AF: 0.00436 AC: 18 AN: 4131

European-Non Finnish (NFE) AF: 0.000133 AC: 112 AN: 839953

Other (OTH) AF: 0.00708 AC: 325 AN: 45928

GnomAD4 genome AF: 0.0301 AC: 3375 AN: 112188 Hom.: 120 Cov.: 22 AF XY: 0.0265 AC XY: 910 AN XY: 34354

African (AFR) AF: 0.104 AC: 3204 AN: 30797

American (AMR) AF: 0.0115 AC: 122 AN: 10631

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2655

East Asian (EAS) AF: 0.00 AC: 0 AN: 3571

South Asian (SAS) AF: 0.00111 AC: 3 AN: 2714

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6154

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 215

European-Non Finnish (NFE) AF: 0.000301 AC: 16 AN: 53240

Other (OTH) AF: 0.0196 AC: 30 AN: 1527

Alfa AF: 0.0159 Hom.: 82

Bravo AF: 0.0349

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	4	not specified (4)
-	-	1	Kidney disorder (1)
-	-	1	X-linked Alport syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	7.6
DANN	Benign	0.73
PhyloP100		-0.15
Mutation Taster		=98/2	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: rs61735627; hg19: chrX-107909790;