rs150209221

Variant names:

• chr10-86706648-A-G
• rs150209221
• NM_007078.3:c.1014A>G

Your query was ambiguous. Multiple possible variants found:

• chr10-86706648-A-G
• chr10-86706648-A-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_007078.3(LDB3):​c.1014A>G​(p.Thr338Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000733 in 1,613,100 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00038 (3 hom.)
• Consequence: LDB3 NM_007078.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.192
• Publications: 1 publications found

Genes affected

LDB3 (HGNC:15710): (LIM domain binding 3) This gene encodes a PDZ domain-containing protein. PDZ motifs are modular protein-protein interaction domains consisting of 80-120 amino acid residues. PDZ domain-containing proteins interact with each other in cytoskeletal assembly or with other proteins involved in targeting and clustering of membrane proteins. The protein encoded by this gene interacts with alpha-actinin-2 through its N-terminal PDZ domain and with protein kinase C via its C-terminal LIM domains. The LIM domain is a cysteine-rich motif defined by 50-60 amino acids containing two zinc-binding modules. This protein also interacts with all three members of the myozenin family. Mutations in this gene have been associated with myofibrillar myopathy and dilated cardiomyopathy. Alternatively spliced transcript variants encoding different isoforms have been identified; all isoforms have N-terminal PDZ domains while only longer isoforms (1, 2 and 5) have C-terminal LIM domains. [provided by RefSeq, Jan 2010]

LDB3 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD, AR Classification: STRONG, LIMITED Submitted by: ClinGen
• myofibrillar myopathy 4

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial dilated cardiomyopathy

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 10-86706648-A-G is Benign according to our data. Variant chr10-86706648-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 45509.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.192 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00412 (627/152298) while in subpopulation AFR AF = 0.0143 (594/41564). AF 95% confidence interval is 0.0133. There are 7 homozygotes in GnomAd4. There are 289 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007078.3. 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
	LDB3	NM_007078.3	MANE Select	c.1014A>G	p.Thr338Thr	synonymous	Exon 8 of 14	NP_009009.1	O75112-1
	LDB3	NM_001368066.1		c.873A>G	p.Thr291Thr	synonymous	Exon 9 of 15	NP_001354995.1	A0A8I5KV04
	LDB3	NM_001171610.2		c.1101-3257A>G		intron	N/A	NP_001165081.1	O75112-7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDB3	ENST00000361373.9	TSL:1 MANE Select	c.1014A>G	p.Thr338Thr	synonymous	Exon 8 of 14	ENSP00000355296.3	O75112-1
	LDB3	ENST00000945680.1		c.1218A>G	p.Thr406Thr	synonymous	Exon 8 of 14	ENSP00000615739.1
	LDB3	ENST00000871464.1		c.1014A>G	p.Thr338Thr	synonymous	Exon 8 of 15	ENSP00000541523.1

Frequencies

GnomAD3 genomes AF: 0.00411 AC: 626 AN: 152180 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0143

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00106 AC: 264 AN: 249802 AF XY: 0.000753

Gnomad AFR exome AF: 0.0149

Gnomad AMR exome AF: 0.000550

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000356

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000381 AC: 556 AN: 1460802 Hom.: 3 Cov.: 32 AF XY: 0.000326 AC XY: 237 AN XY: 726738

African (AFR) AF: 0.0140 AC: 467 AN: 33476

American (AMR) AF: 0.000559 AC: 25 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52558

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000288 AC: 32 AN: 1111892

Other (OTH) AF: 0.000497 AC: 30 AN: 60368

GnomAD4 genome AF: 0.00412 AC: 627 AN: 152298 Hom.: 7 Cov.: 32 AF XY: 0.00388 AC XY: 289 AN XY: 74470

African (AFR) AF: 0.0143 AC: 594 AN: 41564

American (AMR) AF: 0.00176 AC: 27 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68012

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.000358 Hom.: 0

Bravo AF: 0.00462

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	LDB3-related disorder (1)
-	-	1	Myofibrillar myopathy 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	8.9
DANN	Benign	0.62
PhyloP100		0.19
Mutation Taster		=100/0	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: rs150209221; hg19: chr10-88466405;