rs762334954

Positions:

• chr2-219568063-G-GT

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_015311.3(OBSL1):​c.1273_1274insA​(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:11
• Conservation: PhyloP100: 0.537

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-219568063-G-GT is Pathogenic according to our data. Variant chr2-219568063-G-GT is described in ClinVar as [Pathogenic]. Clinvar id is 195306.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OBSL1	NM_015311.3	c.1273_1274insA	p.Thr425AsnfsTer40	frameshift_variant	2/21	ENST00000404537.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OBSL1	ENST00000404537.6	c.1273_1274insA	p.Thr425AsnfsTer40	frameshift_variant	2/21	1	NM_015311.3	P1

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

GnomAD3 exomes AF: 0.000162 AC: 40 AN: 247272 Hom.: 0 AF XY: 0.000149 AC XY: 20 AN XY: 134306

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 SAS exome AF: 0.000164

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

Gnomad4 AFR exome AF: 0.0000898

Gnomad4 AMR exome AF: 0.0000896

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000186

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000451

Gnomad4 OTH exome AF: 0.000249

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

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000196 Hom.: 0

Bravo AF: 0.000147

EpiCase AF: 0.000273

EpiControl AF: 0.000415

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

3M syndrome 2 Pathogenic:7

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	Suma Genomics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The frameshift variant has been reported previously in homozygous state in a patient who presented with prenatal growth retardation and short stature (Keskin M. et al., 2019). This variant is reported with the allele frequency (0.02%) in the gnomad and novel in 1000 genome database. It has been submitted to the ClinVar as a Pathogenic variant. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Pediatric Endocrinology, Ankara Etlik City Hospital	-	Molecular analysis of the OBSL1 gene identified a frameshift variant (c.1273dup; p.Thr425fs) in seven patients with clinical features consistent with 3M syndrome, six of whom were in homozygous and one was in compound heterozygous state. This variant results in a premature stop codon leading to truncation of the protein or nonsense mediated decay. Also, loss-of-function variants in OBSL1 gene have been determined to be deleterious. The detected variant has been associated with 3M syndrome in the literature previously. This variant was classified as pathogenic according to the ACMG guidelines. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 24, 2019	Variant summary: OBSL1 c.1273dupA (p.Thr425AsnfsX40) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00016 in 247272 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in OBSL1 causing 3-M syndrome 2 (0.00016 vs 0.0011), allowing no conclusion about variant significance. c.1273dupA has been reported in the literature in multiple homozygous- and compound heterozygous individuals affected with 3-M syndrome 2 (e.g. Hanson_2009, Hu_2017). These data indicate that the variant is very likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Feb 23, 2023	A heterozygous single base pair duplication in exon 2 of the OBSL1 gene that results in a frameshift and premature truncation of the protein 40 amino acids downstream to codon 425 (p.Thr425AsnfsTer40) was detected. The p.Thr425AsnfsTer40 variant has not been reported in the 1000 genomes databases and has a minor allele frequency of 0.01% in the gnomAD database. The in silico predictions of the variant are damaging by MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic. -
Pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Jun 10, 2015	The OBSL1 variant (c.1273dupA; p.T425fs) is considered pathogenic because it is a frameshift variant predicted to result in a truncated protein containing only one-third of the normal protein. This is a common OBSL1 variant associated with 3-M syndrome reported in 6 families (Huber et al. 2010, PMID 19877176) and 6 families (Hanson et al. 2009, PMID 19481195) mostly in the homozygous state in consanguineous families. This variant is present in 17 alleles out of 121632 alleles in ExAC. Another frameshift variant has been reported downstream of this position -

not provided Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The OBSL1 p.Thr425Asnfs*40 variant was identified in 25 of 50 proband chromosomes (frequency: 0.5) from 25 families with Miller-McKusick-Malvaux (3-M) syndrome (Hanson_2009_PMID:19481195; Huber_2010_PMID:19877176; Marshall_2015_PMID:25923536; Keskin_2017_PMID:27796265). The variant was identified in dbSNP (ID: rs762334954) and ClinVar (classifed as pathogenic by EGL Genetics, Division of Human Genetics, Children's Hospital of Philadelphia and OMIM) but was not identified in Cosmic or LOVD 3.0. The variant was identified in control databases in 46 of 278660 chromosomes at a frequency of 0.000165 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 36 of 126596 chromosomes (freq: 0.000284), South Asian in 5 of 30580 chromosomes (freq: 0.000164), Latino in 4 of 35350 chromosomes (freq: 0.000113) and African in 1 of 24184 chromosomes (freq: 0.000041), but was not observed in the Ashkenazi Jewish, East Asian, European (Finnish) or Other populations. The c.1273dup variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 425 and leads to a premature stop codon 40 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the OBSL1 gene are an established mechanism of disease in 3-M syndrome and are known to cause the disorder in the homozygous or compound heterozygous state. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 12, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2022	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 19481195, 25923536, 27796265, 28969986, 29595812, 34597859, 19877176, 34426522, 31589614, 33258289, 33135300, 34006472) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 01, 2022	This sequence change creates a premature translational stop signal (p.Thr425Asnfs*40) in the OBSL1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in OBSL1 are known to be pathogenic (PMID: 19481195, 19877176). This variant is present in population databases (rs762334954, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with 3-M syndrome (PMID: 19481195, 25923536, 27796265). This variant is also known as c.1273insA, p.T45Nfs*40. ClinVar contains an entry for this variant (Variation ID: 195306). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs762334954; hg19: chr2-220432785;