rs3747408

Variant names:

• chrX-108606846-G-A
• rs3747408
• NM_033380.3:c.2349G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-108606846-G-A
• chrX-108606846-G-C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_033380.3(COL4A5):​c.2349G>A​(p.Pro783Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0242 in 1,208,260 control chromosomes in the GnomAD database, including 2,715 homozygotes. There are 8,298 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P783P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.10 (1298 hom., 3192 hem., cov: 22)
  • Exomes 𝑓: 0.016 (1417 hom. 5106 hem.)
• Consequence: COL4A5 NM_033380.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.0140
• 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant X-108606846-G-A is Benign according to our data. Variant chrX-108606846-G-A is described in ClinVar as Benign. ClinVar VariationId is 24511.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.014 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.331 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.2349G>A	p.Pro783Pro	synonymous	Exon 29 of 53	NP_203699.1	P29400-2
	COL4A5	NM_000495.5		c.2349G>A	p.Pro783Pro	synonymous	Exon 29 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.2349G>A	p.Pro783Pro	synonymous	Exon 29 of 53	ENSP00000331902.7	P29400-2
	COL4A5	ENST00000483338.1	TSL:1	c.1173G>A	p.Pro391Pro	synonymous	Exon 13 of 20	ENSP00000495685.1	Q49AM6
	COL4A5	ENST00000949143.1		c.2349G>A	p.Pro783Pro	synonymous	Exon 29 of 51	ENSP00000619202.1

Frequencies

GnomAD3 genomes AF: 0.104 AC: 11569 AN: 110925 Hom.: 1298 Cov.: 22

Gnomad AFR AF: 0.337

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0568

Gnomad ASJ AF: 0.00303

Gnomad EAS AF: 0.147

Gnomad SAS AF: 0.0215

Gnomad FIN AF: 0.000168

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00132

Gnomad OTH AF: 0.0919

GnomAD2 exomes AF: 0.0454 AC: 8307 AN: 183121 AF XY: 0.0344

Gnomad AFR exome AF: 0.341

Gnomad AMR exome AF: 0.0438

Gnomad ASJ exome AF: 0.00374

Gnomad EAS exome AF: 0.151

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000845

Gnomad OTH exome AF: 0.0239

GnomAD4 exome AF: 0.0161 AC: 17647 AN: 1097288 Hom.: 1417 Cov.: 30 AF XY: 0.0141 AC XY: 5106 AN XY: 362670

African (AFR) AF: 0.340 AC: 8984 AN: 26388

American (AMR) AF: 0.0470 AC: 1654 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00361 AC: 70 AN: 19379

East Asian (EAS) AF: 0.124 AC: 3730 AN: 30201

South Asian (SAS) AF: 0.0150 AC: 814 AN: 54122

European-Finnish (FIN) AF: 0.000173 AC: 7 AN: 40533

Middle Eastern (MID) AF: 0.0116 AC: 48 AN: 4130

European-Non Finnish (NFE) AF: 0.000607 AC: 511 AN: 841270

Other (OTH) AF: 0.0397 AC: 1829 AN: 46058

GnomAD4 genome AF: 0.104 AC: 11579 AN: 110972 Hom.: 1298 Cov.: 22 AF XY: 0.0960 AC XY: 3192 AN XY: 33242

African (AFR) AF: 0.337 AC: 10204 AN: 30313

American (AMR) AF: 0.0565 AC: 591 AN: 10458

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

East Asian (EAS) AF: 0.146 AC: 511 AN: 3494

South Asian (SAS) AF: 0.0212 AC: 56 AN: 2640

European-Finnish (FIN) AF: 0.000168 AC: 1 AN: 5958

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

European-Non Finnish (NFE) AF: 0.00132 AC: 70 AN: 53054

Other (OTH) AF: 0.0908 AC: 138 AN: 1520

Alfa AF: 0.0452 Hom.: 503

Bravo AF: 0.121

EpiCase AF: 0.000818

EpiControl AF: 0.000830

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	7.1
DANN	Benign	0.66
PhyloP100		0.014
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs3747408; hg19: chrX-107850076; COSMIC: COSV60358321;