NM_015311.3:c.2168G>A

Variant names:

• chr2-219565481-C-T
• rs1039898
• NM_015311.3:c.2168G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015311.3(OBSL1):​c.2168G>A​(p.Arg723Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.886 in 1,610,938 control chromosomes in the GnomAD database, including 635,987 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.82 (52394 hom., cov: 32)
  • Exomes 𝑓: 0.89 (583593 hom.)
• Consequence: OBSL1 NM_015311.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.308
• Publications: 36 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.506006E-7).
• BP6: Variant 2-219565481-C-T is Benign according to our data. Variant chr2-219565481-C-T is described in ClinVar as Benign. ClinVar VariationId is 334508.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.899 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OBSL1	NM_015311.3	MANE Select	c.2168G>A	p.Arg723Lys	missense	Exon 6 of 21	NP_056126.1	O75147-3
	OBSL1	NM_001173431.2		c.2168G>A	p.Arg723Lys	missense	Exon 6 of 14	NP_001166902.1	O75147-4
	OBSL1	NM_001173408.2		c.2168G>A	p.Arg723Lys	missense	Exon 6 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.2168G>A	p.Arg723Lys	missense	Exon 6 of 21	ENSP00000385636.1	O75147-3
	OBSL1	ENST00000373873.8	TSL:1	c.2168G>A	p.Arg723Lys	missense	Exon 6 of 9	ENSP00000362980.4	O75147-2
	OBSL1	ENST00000953546.1		c.2168G>A	p.Arg723Lys	missense	Exon 6 of 21	ENSP00000623605.1

Frequencies

GnomAD3 genomes AF: 0.821 AC: 124853 AN: 152046 Hom.: 52358 Cov.: 32

Gnomad AFR AF: 0.635

Gnomad AMI AF: 0.921

Gnomad AMR AF: 0.834

Gnomad ASJ AF: 0.862

Gnomad EAS AF: 0.904

Gnomad SAS AF: 0.836

Gnomad FIN AF: 0.920

Gnomad MID AF: 0.820

Gnomad NFE AF: 0.904

Gnomad OTH AF: 0.842

GnomAD2 exomes AF: 0.867 AC: 214295 AN: 247090 AF XY: 0.871

Gnomad AFR exome AF: 0.629

Gnomad AMR exome AF: 0.831

Gnomad ASJ exome AF: 0.855

Gnomad EAS exome AF: 0.916

Gnomad FIN exome AF: 0.920

Gnomad NFE exome AF: 0.904

Gnomad OTH exome AF: 0.872

GnomAD4 exome AF: 0.893 AC: 1302647 AN: 1458774 Hom.: 583593 Cov.: 61 AF XY: 0.892 AC XY: 647501 AN XY: 725786

African (AFR) AF: 0.622 AC: 20809 AN: 33476

American (AMR) AF: 0.836 AC: 37382 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.857 AC: 22398 AN: 26136

East Asian (EAS) AF: 0.886 AC: 35185 AN: 39700

South Asian (SAS) AF: 0.838 AC: 72297 AN: 86252

European-Finnish (FIN) AF: 0.916 AC: 46315 AN: 50574

Middle Eastern (MID) AF: 0.855 AC: 4931 AN: 5768

European-Non Finnish (NFE) AF: 0.909 AC: 1010302 AN: 1111808

Other (OTH) AF: 0.879 AC: 53028 AN: 60340

GnomAD4 genome AF: 0.821 AC: 124942 AN: 152164 Hom.: 52394 Cov.: 32 AF XY: 0.822 AC XY: 61146 AN XY: 74382

African (AFR) AF: 0.635 AC: 26357 AN: 41476

American (AMR) AF: 0.834 AC: 12744 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.862 AC: 2992 AN: 3472

East Asian (EAS) AF: 0.904 AC: 4676 AN: 5174

South Asian (SAS) AF: 0.837 AC: 4030 AN: 4812

European-Finnish (FIN) AF: 0.920 AC: 9766 AN: 10612

Middle Eastern (MID) AF: 0.816 AC: 240 AN: 294

European-Non Finnish (NFE) AF: 0.904 AC: 61518 AN: 68014

Other (OTH) AF: 0.843 AC: 1779 AN: 2110

Alfa AF: 0.871 Hom.: 63605

Bravo AF: 0.808

TwinsUK AF: 0.916 AC: 3395

ALSPAC AF: 0.909 AC: 3504

ESP6500AA AF: 0.672 AC: 2746

ESP6500EA AF: 0.904 AC: 7582

ExAC AF: 0.865 AC: 104545

Asia WGS AF: 0.857 AC: 2981 AN: 3478

EpiCase AF: 0.903

EpiControl AF: 0.901

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	3.4
DANN	Benign	0.69
DEOGEN2	Benign	0.0091	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.11	T
MetaRNN	Benign	7.5e-7	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.97	N
PhyloP100		-0.31
PrimateAI	Benign	0.33	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.049
Sift	Benign	1.0	T
Sift4G	Benign	0.93	T
Polyphen		0.0	B
Vest4		0.039
MPC		0.16
ClinPred		0.00028	T
GERP RS		2.1
Varity_R		0.069
gMVP		0.49
Mutation Taster		=99/1	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: rs1039898; hg19: chr2-220430203; COSMIC: COSV54726542; COSMIC: COSV54726542;