rs529479786

Variant names:

• chr2-188995688-T-C
• rs529479786
• NM_000090.4:c.1510-4T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 2P and 12B. PM2 BP4_Strong BP6_Very_Strong

The NM_000090.4(COL3A1):​c.1510-4T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,398,760 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: COL3A1 NM_000090.4 splice_region, intron
• Scores: Splicing: ADA: 0.00003239
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.664
• Publications: 0 publications found

Genes affected

COL3A1 (HGNC:2201): (collagen type III alpha 1 chain) This gene encodes the pro-alpha1 chains of type III collagen, a fibrillar collagen that is found in extensible connective tissues such as skin, lung, uterus, intestine and the vascular system, frequently in association with type I collagen. Mutations in this gene are associated with Ehlers-Danlos syndrome type IV, and with aortic and arterial aneurysms. [provided by R. Dalgleish, Feb 2008]

MIR3606 (HGNC:38881): (microRNA 3606) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 2-188995688-T-C is Benign according to our data. Variant chr2-188995688-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1119668.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000090.4. 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
	COL3A1	NM_000090.4	MANE Select	c.1510-4T>C		splice_region intron	N/A	NP_000081.2	P02461-1
	MIR3606	NR_037401.1		n.59T>C		non_coding_transcript_exon	Exon 1 of 1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL3A1	ENST00000304636.9	TSL:1 MANE Select	c.1510-4T>C		splice_region intron	N/A	ENSP00000304408.4	P02461-1
	COL3A1	ENST00000450867.2	TSL:1	c.1411-4T>C		splice_region intron	N/A	ENSP00000415346.2	H7C435
	COL3A1	ENST00000879201.1		c.1501-4T>C		splice_region intron	N/A	ENSP00000549260.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1398760 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 690206

African (AFR) AF: 0.00 AC: 0 AN: 31610

American (AMR) AF: 0.00 AC: 0 AN: 35930

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25170

East Asian (EAS) AF: 0.00 AC: 0 AN: 35872

South Asian (SAS) AF: 0.00 AC: 0 AN: 79208

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5532

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078128

Other (OTH) AF: 0.0000173 AC: 1 AN: 57940

GnomAD4 genome Cov.: 31

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Ehlers-Danlos syndrome, type 4 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.21
DANN	Benign	0.53
PhyloP100		-0.66

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000032
dbscSNV1_RF	Benign	0.0040
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: rs529479786; hg19: chr2-189860414;