chr2-219559765-G-A

Variant names:

• chr2-219559765-G-A
• rs1039900
• NM_015311.3:c.2954-268C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_015311.3(OBSL1):​c.2954-268C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.432 in 461,726 control chromosomes in the GnomAD database, including 45,163 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.47 (16998 hom., cov: 32)
  • Exomes 𝑓: 0.41 (28165 hom.)
• Consequence: OBSL1 NM_015311.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0540
• Publications: 6 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• 3-M syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000269068 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 2-219559765-G-A is Benign according to our data. Variant chr2-219559765-G-A is described in ClinVar as Benign. ClinVar VariationId is 1283559.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.534 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OBSL1	NM_015311.3	MANE Select	c.2954-268C>T		intron	N/A	NP_056126.1
	OBSL1	NM_001173431.2		c.2954-268C>T		intron	N/A	NP_001166902.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OBSL1	ENST00000404537.6	TSL:1 MANE Select	c.2954-268C>T		intron	N/A	ENSP00000385636.1
	OBSL1	ENST00000953546.1		c.2966-268C>T		intron	N/A	ENSP00000623605.1
	OBSL1	ENST00000953548.1		c.2897-268C>T		intron	N/A	ENSP00000623607.1

Frequencies

GnomAD3 genomes AF: 0.467 AC: 70859 AN: 151738 Hom.: 16981 Cov.: 32

Gnomad AFR AF: 0.540

Gnomad AMI AF: 0.466

Gnomad AMR AF: 0.507

Gnomad ASJ AF: 0.335

Gnomad EAS AF: 0.406

Gnomad SAS AF: 0.252

Gnomad FIN AF: 0.462

Gnomad MID AF: 0.380

Gnomad NFE AF: 0.443

Gnomad OTH AF: 0.434

GnomAD4 exome AF: 0.415 AC: 128518 AN: 309872 Hom.: 28165 AF XY: 0.407 AC XY: 64822 AN XY: 159418

African (AFR) AF: 0.528 AC: 5521 AN: 10460

American (AMR) AF: 0.519 AC: 6498 AN: 12518

Ashkenazi Jewish (ASJ) AF: 0.314 AC: 3310 AN: 10552

East Asian (EAS) AF: 0.335 AC: 8248 AN: 24630

South Asian (SAS) AF: 0.245 AC: 5214 AN: 21292

European-Finnish (FIN) AF: 0.447 AC: 8715 AN: 19510

Middle Eastern (MID) AF: 0.384 AC: 565 AN: 1472

European-Non Finnish (NFE) AF: 0.434 AC: 82532 AN: 190348

Other (OTH) AF: 0.415 AC: 7915 AN: 19090

GnomAD4 genome AF: 0.467 AC: 70917 AN: 151854 Hom.: 16998 Cov.: 32 AF XY: 0.464 AC XY: 34477 AN XY: 74226

African (AFR) AF: 0.540 AC: 22335 AN: 41388

American (AMR) AF: 0.507 AC: 7741 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.335 AC: 1164 AN: 3470

East Asian (EAS) AF: 0.406 AC: 2098 AN: 5164

South Asian (SAS) AF: 0.253 AC: 1215 AN: 4804

European-Finnish (FIN) AF: 0.462 AC: 4868 AN: 10530

Middle Eastern (MID) AF: 0.384 AC: 113 AN: 294

European-Non Finnish (NFE) AF: 0.442 AC: 30061 AN: 67940

Other (OTH) AF: 0.430 AC: 903 AN: 2102

Alfa AF: 0.407 Hom.: 2505

Bravo AF: 0.476

Asia WGS AF: 0.322 AC: 1129 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.2
DANN	Benign	0.50
PhyloP100		0.054
PromoterAI		-0.013	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs1039900; hg19: chr2-220424487;