chr2-219568063-G-GT

Variant names:

• chr2-219568063-G-GT
• rs762334954
• NM_015311.3:c.1273dupA

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_015311.3(OBSL1):​c.1273dupA​(p.Thr425AsnfsTer40) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000345 in 1,609,670 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00037 (1 hom.)
• Consequence: OBSL1 NM_015311.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 0.537
• Publications: 14 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]

OBSL1 Gene-Disease associations (from GenCC):

• 3M syndrome 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• 3-M syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 2-219568063-G-GT is Pathogenic according to our data. Variant chr2-219568063-G-GT is described in ClinVar as Pathogenic. ClinVar VariationId is 195306.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1273dupA	p.Thr425AsnfsTer40	frameshift	Exon 2 of 21	NP_056126.1	O75147-3
	OBSL1	NM_001173431.2		c.1273dupA	p.Thr425AsnfsTer40	frameshift	Exon 2 of 14	NP_001166902.1	O75147-4
	OBSL1	NM_001173408.2		c.1273dupA	p.Thr425AsnfsTer40	frameshift	Exon 2 of 9	NP_001166879.1	O75147-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OBSL1	ENST00000404537.6	TSL:1 MANE Select	c.1273dupA	p.Thr425AsnfsTer40	frameshift	Exon 2 of 21	ENSP00000385636.1	O75147-3
	OBSL1	ENST00000373873.8	TSL:1	c.1273dupA	p.Thr425AsnfsTer40	frameshift	Exon 2 of 9	ENSP00000362980.4	O75147-2
	OBSL1	ENST00000953546.1		c.1273dupA	p.Thr425AsnfsTer40	frameshift	Exon 2 of 21	ENSP00000623605.1

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152226 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.000206

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000162 AC: 40 AN: 247272 AF XY: 0.000149

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000870

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000288

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000369 AC: 538 AN: 1457326 Hom.: 1 Cov.: 36 AF XY: 0.000354 AC XY: 256 AN XY: 723920

African (AFR) AF: 0.0000898 AC: 3 AN: 33410

American (AMR) AF: 0.0000896 AC: 4 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39548

South Asian (SAS) AF: 0.000186 AC: 16 AN: 86210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53082

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.000451 AC: 500 AN: 1108384

Other (OTH) AF: 0.000249 AC: 15 AN: 60168

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152344 Hom.: 0 Cov.: 32 AF XY: 0.0000805 AC XY: 6 AN XY: 74500

African (AFR) AF: 0.0000481 AC: 2 AN: 41578

American (AMR) AF: 0.0000653 AC: 1 AN: 15310

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

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

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: 0.000206 AC: 14 AN: 68030

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000196 Hom.: 0

Bravo AF: 0.000147

EpiCase AF: 0.000273

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
9	-	-	3M syndrome 2 (9)
4	-	-	not provided (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.54
Mutation Taster		=1/199	disease causing (ClinVar)

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: rs762334954; hg19: chr2-220432785; COSMIC: COSV54715153; COSMIC: COSV54715153;