rs766548555

Variant names:

• chr2-219557472-C-A
• rs766548555
• NM_015311.3:c.3937G>T

Your query was ambiguous. Multiple possible variants found:

• chr2-219557472-C-A
• chr2-219557472-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_015311.3(OBSL1):​c.3937G>T​(p.Gly1313Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000786 in 1,399,862 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1313R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000079 (0 hom.)
• Consequence: OBSL1 NM_015311.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.627
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• 3-M syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000269068 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.3937G>T	p.Gly1313Trp	missense	Exon 12 of 21	NP_056126.1
	OBSL1	NM_001173431.2		c.3937G>T	p.Gly1313Trp	missense	Exon 12 of 14	NP_001166902.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OBSL1	ENST00000404537.6	TSL:1 MANE Select	c.3937G>T	p.Gly1313Trp	missense	Exon 12 of 21	ENSP00000385636.1
	OBSL1	ENST00000603926.5	TSL:5	c.3937G>T	p.Gly1313Trp	missense	Exon 12 of 14	ENSP00000474519.1
	OBSL1	ENST00000465149.1	TSL:2	n.3168G>T		non_coding_transcript_exon	Exon 11 of 16

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000786 AC: 11 AN: 1399862 Hom.: 0 Cov.: 33 AF XY: 0.0000101 AC XY: 7 AN XY: 691000

African (AFR) AF: 0.00 AC: 0 AN: 31704

American (AMR) AF: 0.00 AC: 0 AN: 36108

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25200

East Asian (EAS) AF: 0.00 AC: 0 AN: 35890

South Asian (SAS) AF: 0.00 AC: 0 AN: 79374

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47224

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5706

European-Non Finnish (NFE) AF: 0.00000925 AC: 10 AN: 1080564

Other (OTH) AF: 0.0000172 AC: 1 AN: 58092

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.045	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		0.63
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.20
Sift	Uncertain	0.024	D
Sift4G	Uncertain	0.014	D
Polyphen		1.0	D
Vest4		0.66
MutPred		0.54		Loss of disorder (P = 0.0023)
MVP		0.32
MPC		0.73
ClinPred		0.94	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.45
Mutation Taster		=76/24	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs766548555; hg19: chr2-220422194;