rs141870580

Variant names:

• chr10-86716348-C-G
• rs141870580
• NM_007078.3:c.1253C>G

Your query was ambiguous. Multiple possible variants found:

• chr10-86716348-C-G
• chr10-86716348-C-T
• chr10-86716348-C-A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4 BS1_Supporting

The NM_007078.3(LDB3):​c.1253C>G​(p.Pro418Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000157 in 1,611,442 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P418L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: LDB3 NM_007078.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 1.34
• 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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3240674).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000132 (20/151766) while in subpopulation NFE AF = 0.000221 (15/67880). AF 95% confidence interval is 0.000135. There are 0 homozygotes in GnomAd4. There are 10 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.1253C>G	p.Pro418Arg	missense	Exon 10 of 14	NP_009009.1	O75112-1
	LDB3	NM_001171610.2		c.1268C>G	p.Pro423Arg	missense	Exon 10 of 14	NP_001165081.1	O75112-7
	LDB3	NM_001368066.1		c.1112C>G	p.Pro371Arg	missense	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.1253C>G	p.Pro418Arg	missense	Exon 10 of 14	ENSP00000355296.3	O75112-1
	LDB3	ENST00000945680.1		c.1457C>G	p.Pro486Arg	missense	Exon 10 of 14	ENSP00000615739.1
	LDB3	ENST00000871464.1		c.1394C>G	p.Pro465Arg	missense	Exon 11 of 15	ENSP00000541523.1

Frequencies

GnomAD3 genomes AF: 0.000132 AC: 20 AN: 151652 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000970

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000221

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.0000967 AC: 24 AN: 248242 AF XY: 0.000126

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000181

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000160 AC: 233 AN: 1459676 Hom.: 0 Cov.: 33 AF XY: 0.000153 AC XY: 111 AN XY: 726120

African (AFR) AF: 0.0000299 AC: 1 AN: 33408

American (AMR) AF: 0.0000671 AC: 3 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86168

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53244

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4138

European-Non Finnish (NFE) AF: 0.000200 AC: 222 AN: 1111958

Other (OTH) AF: 0.000116 AC: 7 AN: 60216

GnomAD4 genome AF: 0.000132 AC: 20 AN: 151766 Hom.: 0 Cov.: 31 AF XY: 0.000135 AC XY: 10 AN XY: 74160

African (AFR) AF: 0.0000967 AC: 4 AN: 41352

American (AMR) AF: 0.00 AC: 0 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.00 AC: 0 AN: 4774

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 67880

Other (OTH) AF: 0.000475 AC: 1 AN: 2106

Alfa AF: 0.0000559 Hom.: 0

Bravo AF: 0.000110

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000124 AC: 15

EpiCase AF: 0.000382

EpiControl AF: 0.000711

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not specified (2)
-	1	-	Cardiovascular phenotype (1)
-	1	-	Dilated cardiomyopathy 1C;C4721886:Myofibrillar myopathy 4 (1)
-	1	-	Myofibrillar myopathy 4 (1)
-	1	-	not provided (1)
-	1	-	Primary familial dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		1.3
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.16
Sift	Benign	0.13	T
Sift4G	Benign	0.22	T
Polyphen		1.0	D
Vest4		0.62
MVP		0.82
MPC		0.46
ClinPred		0.34	T
GERP RS		3.7
Varity_R		0.11
gMVP		0.48
Mutation Taster		=92/8	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: rs141870580; hg19: chr10-88476105;