chr2-227237968-G-C

Position:

• chr2-227237968-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_000091.5(COL4A3):​c.88G>C​(p.Gly30Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,456,978 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: COL4A3 NM_000091.5 missense, splice_region
• Scores: Splicing: ADA: 0.8609
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.39

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]

MFF-DT (HGNC:41067): (MFF divergent transcript)

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-227237968-G-C is Pathogenic according to our data. Variant chr2-227237968-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 562460.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A3	NM_000091.5	c.88G>C	p.Gly30Arg	missense_variant, splice_region_variant	2/52	ENST00000396578.8	NP_000082.2
MFF-DT	NR_102371.1	n.1681+118C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A3	ENST00000396578.8	c.88G>C	p.Gly30Arg	missense_variant, splice_region_variant	2/52	1	NM_000091.5	ENSP00000379823	P1
MFF-DT	ENST00000439598.6	n.1681+118C>G		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1456978 Hom.: 0 Cov.: 27 AF XY: 0.00000138 AC XY: 1 AN XY: 725120

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.03e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Gharavi Laboratory, Columbia University

Sep 16, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.59	T
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	0.58	D
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.014	D
Polyphen		0.98	D
Vest4		0.61
MutPred		0.40		Gain of solvent accessibility (P = 0.0328);
MVP		0.88
MPC		0.61
ClinPred		0.95	D
GERP RS		4.5
Varity_R		0.34
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.86
dbscSNV1_RF	Benign	0.69
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1559854632; hg19: chr2-228102684;