rs72957510

Variant names:

• chr2-219557964-C-T
• rs72957510
• NM_015311.3:c.3649G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015311.3(OBSL1):​c.3649G>A​(p.Glu1217Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00634 in 1,608,856 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0071 (3 hom., cov: 34)
  • Exomes 𝑓: 0.0063 (37 hom.)
• Consequence: OBSL1 NM_015311.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.773
• Publications: 3 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), G2P, Ambry Genetics
• 3-M syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000269068 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004442841).
• BP6: Variant 2-219557964-C-T is Benign according to our data. Variant chr2-219557964-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 193901.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00711 (1083/152314) while in subpopulation AFR AF = 0.0138 (573/41574). AF 95% confidence interval is 0.0128. There are 3 homozygotes in GnomAd4. There are 497 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

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.3649G>A	p.Glu1217Lys	missense	Exon 11 of 21	NP_056126.1	O75147-3
	OBSL1	NM_001173431.2		c.3649G>A	p.Glu1217Lys	missense	Exon 11 of 14	NP_001166902.1	O75147-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OBSL1	ENST00000404537.6	TSL:1 MANE Select	c.3649G>A	p.Glu1217Lys	missense	Exon 11 of 21	ENSP00000385636.1	O75147-3
	OBSL1	ENST00000953546.1		c.3661G>A	p.Glu1221Lys	missense	Exon 11 of 21	ENSP00000623605.1
	OBSL1	ENST00000953548.1		c.3592G>A	p.Glu1198Lys	missense	Exon 11 of 21	ENSP00000623607.1

Frequencies

GnomAD3 genomes AF: 0.00711 AC: 1082 AN: 152196 Hom.: 3 Cov.: 34

Gnomad AFR AF: 0.0138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00235

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00216

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00612

Gnomad OTH AF: 0.00525

GnomAD2 exomes AF: 0.00514 AC: 1191 AN: 231816 AF XY: 0.00494

Gnomad AFR exome AF: 0.0162

Gnomad AMR exome AF: 0.00191

Gnomad ASJ exome AF: 0.00280

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00269

Gnomad NFE exome AF: 0.00719

Gnomad OTH exome AF: 0.00416

GnomAD4 exome AF: 0.00626 AC: 9118 AN: 1456542 Hom.: 37 Cov.: 65 AF XY: 0.00618 AC XY: 4476 AN XY: 724590

African (AFR) AF: 0.0151 AC: 504 AN: 33426

American (AMR) AF: 0.00220 AC: 97 AN: 44132

Ashkenazi Jewish (ASJ) AF: 0.00207 AC: 54 AN: 26036

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39572

South Asian (SAS) AF: 0.00234 AC: 201 AN: 86000

European-Finnish (FIN) AF: 0.00279 AC: 141 AN: 50556

Middle Eastern (MID) AF: 0.00469 AC: 27 AN: 5756

European-Non Finnish (NFE) AF: 0.00701 AC: 7788 AN: 1110858

Other (OTH) AF: 0.00507 AC: 305 AN: 60206

GnomAD4 genome AF: 0.00711 AC: 1083 AN: 152314 Hom.: 3 Cov.: 34 AF XY: 0.00667 AC XY: 497 AN XY: 74472

African (AFR) AF: 0.0138 AC: 573 AN: 41574

American (AMR) AF: 0.00235 AC: 36 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4832

European-Finnish (FIN) AF: 0.00216 AC: 23 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00612 AC: 416 AN: 68004

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.00738 Hom.: 6

Bravo AF: 0.00773

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00597 AC: 23

ESP6500AA AF: 0.0106 AC: 40

ESP6500EA AF: 0.00551 AC: 45

ExAC AF: 0.00553 AC: 666

Asia WGS AF: 0.00173 AC: 7 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	3M syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	14
DANN	Uncertain	1.0
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.99	L
PhyloP100		0.77
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.38	N
REVEL	Benign	0.032
Sift	Benign	0.038	D
Sift4G	Benign	0.54	T
Polyphen		0.99	D
Vest4		0.10
MVP		0.27
MPC		0.19
ClinPred		0.0087	T
GERP RS		1.4
Varity_R		0.077
gMVP		0.43
Mutation Taster		=96/4	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: rs72957510; hg19: chr2-220422686; COSMIC: COSV105026433; COSMIC: COSV105026433;