rs397517208

Variant names:

• chr10-86716412-C-T
• rs397517208
• NM_007078.3:c.1317C>T
• LDB3 p.Pro439Pro

Your query was ambiguous. Multiple possible variants found:

• chr10-86716412-C-T
• chr10-86716412-C-A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS1

The NM_007078.3(LDB3):​c.1317C>T​(p.Pro439Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000375 in 1,546,088 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0000071 (0 hom., cov: 19)
  • Exomes 𝑓: 0.000041 (1 hom.)
• Consequence: LDB3 NM_007078.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.151
• 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 10-86716412-C-T is Benign according to our data. Variant chr10-86716412-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 45513.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.151 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0000406 (57/1405090) while in subpopulation SAS AF = 0.000646 (52/80538). AF 95% confidence interval is 0.000505. There are 1 homozygotes in GnomAdExome4. There are 42 alleles in the male GnomAdExome4 subpopulation. Median coverage is 38. This position passed quality control check.

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.1317C>T	p.Pro439Pro	synonymous	Exon 10 of 14	NP_009009.1	O75112-1
	LDB3	NM_001171610.2		c.1332C>T	p.Pro444Pro	synonymous	Exon 10 of 14	NP_001165081.1	O75112-7
	LDB3	NM_001368066.1		c.1176C>T	p.Pro392Pro	synonymous	Exon 11 of 15	NP_001354995.1	A0A8I5KV04

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDB3	ENST00000361373.9	TSL:1 MANE Select	c.1317C>T	p.Pro439Pro	synonymous	Exon 10 of 14	ENSP00000355296.3	O75112-1
	LDB3	ENST00000945680.1		c.1521C>T	p.Pro507Pro	synonymous	Exon 10 of 14	ENSP00000615739.1
	LDB3	ENST00000871464.1		c.1458C>T	p.Pro486Pro	synonymous	Exon 11 of 15	ENSP00000541523.1

Frequencies

GnomAD3 genomes AF: 0.00000709 AC: 1 AN: 140998 Hom.: 0 Cov.: 19

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000243

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000871 AC: 15 AN: 172176 AF XY: 0.000130

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000406 AC: 57 AN: 1405090 Hom.: 1 Cov.: 38 AF XY: 0.0000605 AC XY: 42 AN XY: 694302

African (AFR) AF: 0.0000308 AC: 1 AN: 32460

American (AMR) AF: 0.00 AC: 0 AN: 38084

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25146

East Asian (EAS) AF: 0.00 AC: 0 AN: 37684

South Asian (SAS) AF: 0.000646 AC: 52 AN: 80538

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49350

Middle Eastern (MID) AF: 0.000248 AC: 1 AN: 4040

European-Non Finnish (NFE) AF: 9.26e-7 AC: 1 AN: 1079668

Other (OTH) AF: 0.0000344 AC: 2 AN: 58120

GnomAD4 genome AF: 0.00000709 AC: 1 AN: 140998 Hom.: 0 Cov.: 19 AF XY: 0.0000146 AC XY: 1 AN XY: 68270

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 37452

American (AMR) AF: 0.00 AC: 0 AN: 13988

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3358

East Asian (EAS) AF: 0.00 AC: 0 AN: 4736

South Asian (SAS) AF: 0.000243 AC: 1 AN: 4118

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9748

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 296

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 64544

Other (OTH) AF: 0.00 AC: 0 AN: 1882

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.89
DANN	Benign	0.95
PhyloP100		-0.15

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs397517208;

hg19: chr10-88476169;