rs71473272

Variant names:

• chr10-86687270-T-C
• rs71473272
• NM_001368067.1:c.546T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001368067.1(LDB3):​c.546T>C​(p.Ser182Ser) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00444 in 1,613,964 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0035 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0045 (44 hom.)
• Consequence: LDB3 NM_001368067.1 splice_region, synonymous
• Scores: Splicing: ADA: 0.00001666
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:14
• Conservation: PhyloP100: -0.424
• Publications: 2 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

ENSG00000289258 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 10-86687270-T-C is Benign according to our data. Variant chr10-86687270-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 43880.
• BP7: Synonymous conserved (PhyloP=-0.424 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00352 (536/152202) while in subpopulation SAS AF = 0.0108 (52/4826). AF 95% confidence interval is 0.00844. There are 1 homozygotes in GnomAd4. There are 278 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 44 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001368067.1. 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_001368067.1	MANE Plus Clinical	c.546T>C	p.Ser182Ser	splice_region synonymous	Exon 6 of 9	NP_001354996.1	A0A0S2Z530
	LDB3	NM_007078.3	MANE Select	c.690-4626T>C		intron	N/A	NP_009009.1	O75112-1
	LDB3	NM_001171610.2		c.891T>C	p.Ser297Ser	splice_region synonymous	Exon 6 of 14	NP_001165081.1	O75112-7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDB3	ENST00000263066.11	TSL:1 MANE Plus Clinical	c.546T>C	p.Ser182Ser	splice_region synonymous	Exon 6 of 9	ENSP00000263066.7	O75112-6
	LDB3	ENST00000372056.8	TSL:1	c.891T>C	p.Ser297Ser	splice_region synonymous	Exon 5 of 8	ENSP00000361126.4	O75112-4
	LDB3	ENST00000372066.8	TSL:1	c.546T>C	p.Ser182Ser	splice_region synonymous	Exon 5 of 8	ENSP00000361136.3	O75112-6

Frequencies

GnomAD3 genomes AF: 0.00352 AC: 535 AN: 152084 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00471

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0106

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00456

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00503 AC: 1253 AN: 249284 AF XY: 0.00589

Gnomad AFR exome AF: 0.000581

Gnomad AMR exome AF: 0.00359

Gnomad ASJ exome AF: 0.0148

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00484

Gnomad OTH exome AF: 0.00677

GnomAD4 exome AF: 0.00453 AC: 6627 AN: 1461762 Hom.: 44 Cov.: 33 AF XY: 0.00489 AC XY: 3559 AN XY: 727192

African (AFR) AF: 0.000568 AC: 19 AN: 33480

American (AMR) AF: 0.00407 AC: 182 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0135 AC: 354 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0122 AC: 1050 AN: 86256

European-Finnish (FIN) AF: 0.000131 AC: 7 AN: 53368

Middle Eastern (MID) AF: 0.0146 AC: 84 AN: 5764

European-Non Finnish (NFE) AF: 0.00414 AC: 4606 AN: 1111940

Other (OTH) AF: 0.00535 AC: 323 AN: 60396

GnomAD4 genome AF: 0.00352 AC: 536 AN: 152202 Hom.: 1 Cov.: 33 AF XY: 0.00374 AC XY: 278 AN XY: 74424

African (AFR) AF: 0.000650 AC: 27 AN: 41522

American (AMR) AF: 0.00471 AC: 72 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0156 AC: 54 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.0108 AC: 52 AN: 4826

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10608

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.00456 AC: 310 AN: 67988

Other (OTH) AF: 0.00568 AC: 12 AN: 2114

Alfa AF: 0.00393 Hom.: 0

Bravo AF: 0.00345

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	5	not provided (5)
-	1	1	Myofibrillar myopathy 4 (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1C (1)
-	1	-	Dilated Cardiomyopathy, Dominant (1)
-	1	-	Left ventricular noncompaction cardiomyopathy (1)
-	1	-	Myofibrillar Myopathy, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	11
DANN	Benign	0.59
PhyloP100		-0.42
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000017
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.010		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: rs71473272; hg19: chr10-88447027; COSMIC: COSV107309439;