rs139271412

Variant names:

• chr2-227164799-C-T
• rs139271412
• NM_000091.5:c.73C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000091.5(COL4A3):​c.73C>T​(p.Pro25Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00165 in 1,518,396 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. P25P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0088 (22 hom., cov: 32)
  • Exomes 𝑓: 0.00085 (16 hom.)
• Consequence: COL4A3 NM_000091.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.671
• Publications: 2 publications found

Genes affected

COL4A3 (HGNC:2204): (collagen type IV alpha 3 chain) Type IV collagen, the major structural component of basement membranes, is a multimeric protein composed of 3 alpha subunits. These subunits are encoded by 6 different genes, alpha 1 through alpha 6, each of which can form a triple helix structure with 2 other subunits to form type IV collagen. This gene encodes alpha 3. In the Goodpasture syndrome, autoantibodies bind to the collagen molecules in the basement membranes of alveoli and glomeruli. The epitopes that elicit these autoantibodies are localized largely to the non-collagenous C-terminal domain of the protein. A specific kinase phosphorylates amino acids in this same C-terminal region and the expression of this kinase is upregulated during pathogenesis. This gene is also linked to an autosomal recessive form of Alport syndrome. The mutations contributing to this syndrome are also located within the exons that encode this C-terminal region. 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. [provided by RefSeq, Jun 2010]

COL4A3 Gene-Disease associations (from GenCC):

• Alport syndrome 3b, autosomal recessive

  Inheritance: AD, AR Classification: DEFINITIVE Submitted by: G2P
• autosomal recessive Alport syndrome

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

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal dominant Alport syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• hematuria, benign familial, 1

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0031597614).
• BP6: Variant 2-227164799-C-T is Benign according to our data. Variant chr2-227164799-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255004.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0088 (1340/152202) while in subpopulation AFR AF = 0.0309 (1285/41548). AF 95% confidence interval is 0.0295. There are 22 homozygotes in GnomAd4. There are 598 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 22 AD,AR,SD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000091.5. 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
	COL4A3	NM_000091.5	MANE Select	c.73C>T	p.Pro25Ser	missense	Exon 1 of 52	NP_000082.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A3	ENST00000396578.8	TSL:1 MANE Select	c.73C>T	p.Pro25Ser	missense	Exon 1 of 52	ENSP00000379823.3

Frequencies

GnomAD3 genomes AF: 0.00880 AC: 1339 AN: 152084 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.0310

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00146 AC: 166 AN: 113982 AF XY: 0.00124

Gnomad AFR exome AF: 0.0402

Gnomad AMR exome AF: 0.00150

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000117

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000712

Gnomad OTH exome AF: 0.00113

GnomAD4 exome AF: 0.000848 AC: 1159 AN: 1366194 Hom.: 16 Cov.: 31 AF XY: 0.000693 AC XY: 467 AN XY: 673604

African (AFR) AF: 0.0317 AC: 918 AN: 28930

American (AMR) AF: 0.00176 AC: 61 AN: 34744

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24484

East Asian (EAS) AF: 0.0000590 AC: 2 AN: 33900

South Asian (SAS) AF: 0.000116 AC: 9 AN: 77622

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33330

Middle Eastern (MID) AF: 0.00125 AC: 5 AN: 4012

European-Non Finnish (NFE) AF: 0.0000485 AC: 52 AN: 1072188

Other (OTH) AF: 0.00197 AC: 112 AN: 56984

GnomAD4 genome AF: 0.00880 AC: 1340 AN: 152202 Hom.: 22 Cov.: 32 AF XY: 0.00804 AC XY: 598 AN XY: 74424

African (AFR) AF: 0.0309 AC: 1285 AN: 41548

American (AMR) AF: 0.00242 AC: 37 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5122

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 67992

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.00519 Hom.: 0

Bravo AF: 0.0104

ExAC AF: 0.000321 AC: 15

Asia WGS AF: 0.00145 AC: 5 AN: 3472

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Alport syndrome (1)
-	-	1	Kidney disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	8.7
DANN	Benign	0.94
DEOGEN2	Benign	0.058	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.33	T
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.67
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.17
Sift	Benign	0.47	T
Sift4G	Benign	0.99	T
Polyphen		0.0010	B
Vest4		0.10
MVP		0.53
MPC		0.21
ClinPred		0.0045	T
GERP RS		3.5
PromoterAI		0.0022	Neutral
Varity_R		0.019
gMVP		0.11
Mutation Taster		=97/3	polymorphism

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: rs139271412; hg19: chr2-228029515;