rs104886345

Variant names:

• chrX-108602961-C-T
• rs104886345
• NM_033380.3:c.2147-3C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-108602961-C-T
• chrX-108602961-C-G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_033380.3(COL4A5):​c.2147-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000219 in 1,050,029 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.000022 (0 hom. 6 hem.)
• Consequence: COL4A5 NM_033380.3 splice_region, intron
• Scores: Splicing: ADA: 0.002200
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.02
• Publications: 1 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant X-108602961-C-T is Benign according to our data. Variant chrX-108602961-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3357915.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Hemizygotes in GnomAdExome4 at 6 XL gene

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.2147-3C>T		splice_region intron	N/A	NP_203699.1	P29400-2
	COL4A5	NM_000495.5		c.2147-3C>T		splice_region 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.2147-3C>T		splice_region intron	N/A	ENSP00000331902.7	P29400-2
	COL4A5	ENST00000483338.1	TSL:1	c.971-3C>T		splice_region intron	N/A	ENSP00000495685.1	Q49AM6
	COL4A5	ENST00000949143.1		c.2147-3C>T		splice_region intron	N/A	ENSP00000619202.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.0000219 AC: 23 AN: 1050029 Hom.: 0 Cov.: 25 AF XY: 0.0000181 AC XY: 6 AN XY: 331139

African (AFR) AF: 0.00 AC: 0 AN: 25416

American (AMR) AF: 0.00 AC: 0 AN: 32191

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18720

East Asian (EAS) AF: 0.00 AC: 0 AN: 29032

South Asian (SAS) AF: 0.00 AC: 0 AN: 50648

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38696

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3601

European-Non Finnish (NFE) AF: 0.0000285 AC: 23 AN: 807479

Other (OTH) AF: 0.00 AC: 0 AN: 44246

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	COL4A5-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	12
DANN	Benign	0.77
PhyloP100		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0022
dbscSNV1_RF	Benign	0.028
SpliceAI score (max)		0.090		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: rs104886345;

hg19: chrX-107846191;