chr2-227002723-G-C

Variant names:

• chr2-227002723-G-C
• rs1054415
• NM_000092.5:c.*4602C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000092.5(COL4A4):​c.*4602C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0769 in 152,710 control chromosomes in the GnomAD database, including 491 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.077 (490 hom., cov: 34)
  • Exomes 𝑓: 0.076 (1 hom.)
• Consequence: COL4A4 NM_000092.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.620
• Publications: 5 publications found

Genes affected

COL4A4 (HGNC:2206): (collagen type IV alpha 4 chain) This gene encodes one of the six subunits of type IV collagen, the major structural component of basement membranes. This particular collagen IV subunit, however, is only found in a subset of basement membranes. 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. Mutations in this gene are associated with type II autosomal recessive Alport syndrome (hereditary glomerulonephropathy) and with familial benign hematuria (thin basement membrane disease). Two transcripts, differing only in their transcription start sites, have been identified for this gene and, as is common for collagen genes, multiple polyadenylation sites are found in the 3' UTR. [provided by RefSeq, Jul 2008]

COL4A4 Gene-Disease associations (from GenCC):

• autosomal recessive Alport syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Ambry Genetics, Myriad Women’s Health, Genomics England PanelApp
• Alport syndrome

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• hematuria, benign familial, 1

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• autosomal dominant Alport syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 2-227002723-G-C is Benign according to our data. Variant chr2-227002723-G-C is described in ClinVar as Benign. ClinVar VariationId is 334637.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.169 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000092.5. 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
	COL4A4	NM_000092.5	MANE Select	c.*4602C>G		3_prime_UTR	Exon 48 of 48	NP_000083.3	P53420

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A4	ENST00000396625.5	TSL:5 MANE Select	c.*4602C>G		3_prime_UTR	Exon 48 of 48	ENSP00000379866.3	P53420

Frequencies

GnomAD3 genomes AF: 0.0769 AC: 11700 AN: 152172 Hom.: 487 Cov.: 34

Gnomad AFR AF: 0.0475

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0697

Gnomad ASJ AF: 0.0854

Gnomad EAS AF: 0.179

Gnomad SAS AF: 0.0984

Gnomad FIN AF: 0.0578

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.0900

Gnomad OTH AF: 0.0842

GnomAD4 exome AF: 0.0762 AC: 32 AN: 420 Hom.: 1 Cov.: 0 AF XY: 0.0547 AC XY: 14 AN XY: 256

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.0749 AC: 31 AN: 414

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 2

Other (OTH) AF: 0.250 AC: 1 AN: 4

GnomAD4 genome AF: 0.0769 AC: 11710 AN: 152290 Hom.: 490 Cov.: 34 AF XY: 0.0760 AC XY: 5661 AN XY: 74470

African (AFR) AF: 0.0474 AC: 1969 AN: 41574

American (AMR) AF: 0.0695 AC: 1064 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0854 AC: 296 AN: 3468

East Asian (EAS) AF: 0.179 AC: 928 AN: 5184

South Asian (SAS) AF: 0.0989 AC: 478 AN: 4832

European-Finnish (FIN) AF: 0.0578 AC: 613 AN: 10602

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.0900 AC: 6123 AN: 68008

Other (OTH) AF: 0.0890 AC: 188 AN: 2112

Alfa AF: 0.0722 Hom.: 45

Bravo AF: 0.0756

Asia WGS AF: 0.145 AC: 503 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Alport syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	7.0
DANN	Benign	0.75
PhyloP100		0.62
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

Other links and lift over

dbSNP: rs1054415; hg19: chr2-227867439;