chr2-219551600-C-T

Variant names:

• chr2-219551600-C-T
• rs757557849
• NM_015311.3:c.5612G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015311.3(OBSL1):​c.5612G>A​(p.Arg1871Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,458,174 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: OBSL1 NM_015311.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.111
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05570522).

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.5612G>A	p.Arg1871Gln	missense	Exon 20 of 21	NP_056126.1	O75147-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OBSL1	ENST00000404537.6	TSL:1 MANE Select	c.5612G>A	p.Arg1871Gln	missense	Exon 20 of 21	ENSP00000385636.1	O75147-3
	OBSL1	ENST00000953546.1		c.5624G>A	p.Arg1875Gln	missense	Exon 20 of 21	ENSP00000623605.1
	OBSL1	ENST00000953548.1		c.5555G>A	p.Arg1852Gln	missense	Exon 20 of 21	ENSP00000623607.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 241138 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1458174 Hom.: 0 Cov.: 33 AF XY: 0.00000276 AC XY: 2 AN XY: 724944

African (AFR) AF: 0.00 AC: 0 AN: 33426

American (AMR) AF: 0.00 AC: 0 AN: 44302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26022

East Asian (EAS) AF: 0.00 AC: 0 AN: 39534

South Asian (SAS) AF: 0.00 AC: 0 AN: 85384

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 52974

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110564

Other (OTH) AF: 0.00 AC: 0 AN: 60206

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000827 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.010	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.080	N
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.056	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.58	N
PhyloP100		0.11
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.58	N
REVEL	Benign	0.064
Sift	Benign	0.66	T
Sift4G	Benign	0.61	T
Polyphen		0.80	P
Vest4		0.18
MutPred		0.36		Loss of sheet (P = 0.1398)
MVP		0.19
MPC		0.19
ClinPred		0.16	T
GERP RS		0.94
Varity_R		0.082
gMVP		0.33
Mutation Taster		=95/5	polymorphism

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: rs757557849; hg19: chr2-220416322; COSMIC: COSV54704271; COSMIC: COSV54704271;