10-86681607-C-T

Variant names:

• chr10-86681607-C-T
• rs45610637
• NM_007078.3:c.493C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_007078.3(LDB3):​c.493C>T​(p.Arg165Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000108 in 1,613,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R165Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000098 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: LDB3 NM_007078.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.263
• Publications: 6 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006264955).
• BP6: Variant 10-86681607-C-T is Benign according to our data. Variant chr10-86681607-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 177802.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000985 (15/152336) while in subpopulation EAS AF = 0.00232 (12/5168). AF 95% confidence interval is 0.00134. There are 0 homozygotes in GnomAd4. There are 7 alleles in the male GnomAd4 subpopulation. Median coverage is 34. 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.493C>T	p.Arg165Trp	missense	Exon 5 of 14	NP_009009.1	O75112-1
	LDB3	NM_001368067.1	MANE Plus Clinical	c.321+1450C>T		intron	N/A	NP_001354996.1	A0A0S2Z530
	LDB3	NM_001171610.2		c.493C>T	p.Arg165Trp	missense	Exon 5 of 14	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.493C>T	p.Arg165Trp	missense	Exon 5 of 14	ENSP00000355296.3	O75112-1
	ENSG00000289258	ENST00000443292.2	TSL:1	c.2002C>T	p.Arg668Trp	missense	Exon 15 of 18	ENSP00000393132.2	C9JWU6
	LDB3	ENST00000372056.8	TSL:1	c.493C>T	p.Arg165Trp	missense	Exon 4 of 8	ENSP00000361126.4	O75112-4

Frequencies

GnomAD3 genomes AF: 0.0000985 AC: 15 AN: 152218 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00232

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000251 AC: 62 AN: 246648 AF XY: 0.000186

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00253

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000452

Gnomad OTH exome AF: 0.000332

GnomAD4 exome AF: 0.000109 AC: 159 AN: 1460670 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 78 AN XY: 726674

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44696

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

East Asian (EAS) AF: 0.000907 AC: 36 AN: 39692

South Asian (SAS) AF: 0.0000928 AC: 8 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52634

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

European-Non Finnish (NFE) AF: 0.0000855 AC: 95 AN: 1111716

Other (OTH) AF: 0.000331 AC: 20 AN: 60354

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152336 Hom.: 0 Cov.: 34 AF XY: 0.0000940 AC XY: 7 AN XY: 74492

African (AFR) AF: 0.00 AC: 0 AN: 41586

American (AMR) AF: 0.00 AC: 0 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00232 AC: 12 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000901 Hom.: 0

Bravo AF: 0.0000982

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000247 AC: 30

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	5.3
DANN	Benign	0.95
DEOGEN2	Benign	0.37	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.0063	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		-0.26
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.013
Sift	Benign	0.086	T
Sift4G	Uncertain	0.027	D
Polyphen		0.0010	B
Vest4		0.18
MVP		0.45
MPC		0.20
ClinPred		0.018	T
GERP RS		-1.9
Varity_R		0.043
gMVP		0.59
Mutation Taster		=97/3	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: rs45610637; hg19: chr10-88441364;