rs199581317

Variant names:

• chr2-227098696-G-A
• rs199581317
• NM_000092.5:c.1202C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PM1 BP6_Very_Strong BS1 BS2

The ENST00000396625.5(COL4A4):​c.1202C>T​(p.Ala401Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00116 in 1,613,376 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/25 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A401A) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00058 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (34 hom.)
• Consequence: COL4A4 ENST00000396625.5 missense, splice_region
• Scores: Splicing: ADA: 0.8343
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.00
• Publications: 3 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), Genomics England PanelApp, G2P, Orphanet, Ambry Genetics, Myriad Women’s Health
• Alport syndrome

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

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in ENST00000396625.5
• BP6: Variant 2-227098696-G-A is Benign according to our data. Variant chr2-227098696-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 504909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000578 (88/152286) while in subpopulation SAS AF = 0.0172 (83/4826). AF 95% confidence interval is 0.0142. There are 2 homozygotes in GnomAd4. There are 66 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD,SD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000396625.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A4	NM_000092.5	MANE Select	c.1202C>T	p.Ala401Val	missense splice_region	Exon 19 of 48	NP_000083.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A4	ENST00000396625.5	TSL:5 MANE Select	c.1202C>T	p.Ala401Val	missense splice_region	Exon 19 of 48	ENSP00000379866.3

Frequencies

GnomAD3 genomes AF: 0.000572 AC: 87 AN: 152168 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0170

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00264 AC: 655 AN: 248526 AF XY: 0.00342

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00389

Gnomad EAS exome AF: 0.000112

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000533

Gnomad OTH exome AF: 0.00216

GnomAD4 exome AF: 0.00122 AC: 1780 AN: 1461090 Hom.: 34 Cov.: 30 AF XY: 0.00176 AC XY: 1283 AN XY: 726922

African (AFR) AF: 0.0000896 AC: 3 AN: 33464

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00310 AC: 81 AN: 26120

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39692

South Asian (SAS) AF: 0.0182 AC: 1569 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53368

Middle Eastern (MID) AF: 0.00434 AC: 25 AN: 5766

European-Non Finnish (NFE) AF: 0.0000171 AC: 19 AN: 1111368

Other (OTH) AF: 0.00133 AC: 80 AN: 60356

GnomAD4 genome AF: 0.000578 AC: 88 AN: 152286 Hom.: 2 Cov.: 32 AF XY: 0.000886 AC XY: 66 AN XY: 74466

African (AFR) AF: 0.00 AC: 0 AN: 41572

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.0172 AC: 83 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68016

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000457 Hom.: 0

Bravo AF: 0.000140

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.00295 AC: 357

Asia WGS AF: 0.00895 AC: 31 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Alport syndrome (2)
-	-	2	not provided (2)
-	-	1	Kidney disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.22	T
MetaRNN	Benign	0.0090	T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.0
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.23
Sift	Benign	0.33	T
Sift4G	Benign	0.30	T
Polyphen		0.0050	B
Vest4		0.16
MVP		0.61
MPC		0.57
ClinPred		0.023	T
GERP RS		2.4
Varity_R		0.054
gMVP		0.17
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.83
dbscSNV1_RF	Pathogenic	0.73
SpliceAI score (max)		0.31		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.31		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs199581317; hg19: chr2-227963412;