rs2273051

Variant names:

• chrX-108666554-A-G
• rs2273051
• NM_033380.3:c.3513A>G
• COL4A5 p.Gln1171Gln

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.3513A>G​(p.Gln1171Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0299 in 1,206,703 control chromosomes in the GnomAD database, including 4,546 homozygotes. There are 10,141 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (2237 hom., 4190 hem., cov: 23)
  • Exomes 𝑓: 0.019 (2309 hom. 5951 hem.)
• Consequence: COL4A5 NM_033380.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 2.25
• Publications: 6 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: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), 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-108666554-A-G is Benign according to our data. Variant chrX-108666554-A-G is described in ClinVar as Benign. ClinVar VariationId is 24640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.26 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.436 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.3513A>G	p.Gln1171Gln	synonymous	Exon 39 of 53	NP_203699.1	P29400-2
	COL4A5	NM_000495.5		c.3513A>G	p.Gln1171Gln	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.3513A>G	p.Gln1171Gln	synonymous	Exon 39 of 53	ENSP00000331902.7	P29400-2
	COL4A5	ENST00000949143.1		c.3525A>G	p.Gln1175Gln	synonymous	Exon 39 of 51	ENSP00000619202.1
	COL4A5	ENST00000361603.7	TSL:2	c.3513A>G	p.Gln1171Gln	synonymous	Exon 39 of 51	ENSP00000354505.2	P29400-1

Frequencies

GnomAD3 genomes AF: 0.134 AC: 15038 AN: 111833 Hom.: 2236 Cov.: 23

Gnomad AFR AF: 0.443

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0665

Gnomad ASJ AF: 0.00302

Gnomad EAS AF: 0.147

Gnomad SAS AF: 0.0236

Gnomad FIN AF: 0.000163

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00163

Gnomad OTH AF: 0.107

GnomAD2 exomes AF: 0.0529 AC: 9226 AN: 174423 AF XY: 0.0360

Gnomad AFR exome AF: 0.444

Gnomad AMR exome AF: 0.0484

Gnomad ASJ exome AF: 0.00381

Gnomad EAS exome AF: 0.146

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00106

Gnomad OTH exome AF: 0.0270

GnomAD4 exome AF: 0.0192 AC: 21073 AN: 1094812 Hom.: 2309 Cov.: 30 AF XY: 0.0165 AC XY: 5951 AN XY: 360648

African (AFR) AF: 0.449 AC: 11806 AN: 26287

American (AMR) AF: 0.0532 AC: 1858 AN: 34955

Ashkenazi Jewish (ASJ) AF: 0.00362 AC: 70 AN: 19338

East Asian (EAS) AF: 0.123 AC: 3692 AN: 30049

South Asian (SAS) AF: 0.0152 AC: 812 AN: 53408

European-Finnish (FIN) AF: 0.000174 AC: 7 AN: 40328

Middle Eastern (MID) AF: 0.0160 AC: 66 AN: 4130

European-Non Finnish (NFE) AF: 0.000737 AC: 619 AN: 840373

Other (OTH) AF: 0.0466 AC: 2143 AN: 45944

GnomAD4 genome AF: 0.135 AC: 15063 AN: 111891 Hom.: 2237 Cov.: 23 AF XY: 0.123 AC XY: 4190 AN XY: 34079

African (AFR) AF: 0.443 AC: 13521 AN: 30543

American (AMR) AF: 0.0662 AC: 703 AN: 10622

Ashkenazi Jewish (ASJ) AF: 0.00302 AC: 8 AN: 2651

East Asian (EAS) AF: 0.146 AC: 518 AN: 3543

South Asian (SAS) AF: 0.0233 AC: 63 AN: 2705

European-Finnish (FIN) AF: 0.000163 AC: 1 AN: 6151

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

European-Non Finnish (NFE) AF: 0.00163 AC: 87 AN: 53247

Other (OTH) AF: 0.106 AC: 162 AN: 1528

Alfa AF: 0.0500 Hom.: 2322

Bravo AF: 0.155

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	2	X-linked Alport syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	7.8
DANN	Benign	0.64
PhyloP100		2.3
Mutation Taster		=100/0	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2273051;

hg19: chrX-107909784;

COSMIC: COSV60358057;

COSMIC: COSV60358057;