2-219550732-C-CTA

Variant names:

• chr2-219550732-C-CTA
• rs538538342
• NM_015311.3:c.*102_*103insTA

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS1_Supporting

The NM_015311.3(OBSL1):​c.*102_*103insTA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000343 in 1,461,816 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0017 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: OBSL1 NM_015311.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0550
• Publications: 1 publications found

Genes affected

OBSL1 (HGNC:29092): (obscurin like cytoskeletal adaptor 1) Cytoskeletal adaptor proteins function in linking the internal cytoskeleton of cells to the cell membrane. This gene encodes a cytoskeletal adaptor protein, which is a member of the Unc-89/obscurin family. The protein contains multiple N- and C-terminal immunoglobulin (Ig)-like domains and a central fibronectin type 3 domain. Mutations in this gene cause 3M syndrome type 2. Alternatively spliced transcript variants encoding different isoforms have been found in this gene. [provided by RefSeq, Mar 2010]

TMEM198 (HGNC:33704): (transmembrane protein 198) Involved in positive regulation of canonical Wnt signaling pathway. Located in cytoplasmic vesicle and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00173 (263/152348) while in subpopulation AFR AF = 0.00609 (253/41576). AF 95% confidence interval is 0.00547. There are 1 homozygotes in GnomAd4. There are 114 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015311.3. 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
	OBSL1	NM_015311.3	MANE Select	c.*102_*103insTA		3_prime_UTR	Exon 21 of 21	NP_056126.1	O75147-3
	TMEM198	NM_001005209.3	MANE Select	c.*878_*879insTA		downstream_gene	N/A	NP_001005209.1	Q66K66
	TMEM198	NM_001303098.2		c.*878_*879insTA		downstream_gene	N/A	NP_001290027.1	Q66K66

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OBSL1	ENST00000404537.6	TSL:1 MANE Select	c.*102_*103insTA		3_prime_UTR	Exon 21 of 21	ENSP00000385636.1	O75147-3
	OBSL1	ENST00000953546.1		c.*102_*103insTA		3_prime_UTR	Exon 21 of 21	ENSP00000623605.1
	OBSL1	ENST00000953548.1		c.*102_*103insTA		3_prime_UTR	Exon 21 of 21	ENSP00000623607.1

Frequencies

GnomAD3 genomes AF: 0.00172 AC: 262 AN: 152230 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00608

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

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: 0.0000147

Gnomad OTH AF: 0.000955

GnomAD4 exome AF: 0.000183 AC: 239 AN: 1309468 Hom.: 0 Cov.: 20 AF XY: 0.000165 AC XY: 107 AN XY: 650034

African (AFR) AF: 0.00634 AC: 190 AN: 29948

American (AMR) AF: 0.000396 AC: 14 AN: 35384

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24138

East Asian (EAS) AF: 0.00 AC: 0 AN: 35568

South Asian (SAS) AF: 0.00 AC: 0 AN: 77074

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48634

Middle Eastern (MID) AF: 0.000376 AC: 2 AN: 5322

European-Non Finnish (NFE) AF: 0.00000801 AC: 8 AN: 998414

Other (OTH) AF: 0.000455 AC: 25 AN: 54986

GnomAD4 genome AF: 0.00173 AC: 263 AN: 152348 Hom.: 1 Cov.: 32 AF XY: 0.00153 AC XY: 114 AN XY: 74492

African (AFR) AF: 0.00609 AC: 253 AN: 41576

American (AMR) AF: 0.000458 AC: 7 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68036

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00128 Hom.: 1

Bravo AF: 0.00212

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	3-M syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.055

Splicing

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

Other links and lift over

dbSNP: rs538538342; hg19: chr2-220415454;