rs372331627

Variant names:

• chr10-86716767-A-G
• rs372331627
• NM_007078.3:c.1672A>G

Your query was ambiguous. Multiple possible variants found:

• chr10-86716767-A-G
• chr10-86716767-A-C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_007078.3(LDB3):​c.1672A>G​(p.Ile558Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000158 in 1,604,004 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00017 (5 hom.)
• Consequence: LDB3 NM_007078.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:8
• Conservation: PhyloP100: 9.11
• Publications: 7 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.062360555).
• BP6: Variant 10-86716767-A-G is Benign according to our data. Variant chr10-86716767-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45532.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000723 (11/152220) while in subpopulation SAS AF = 0.00124 (6/4820). AF 95% confidence interval is 0.000542. There are 0 homozygotes in GnomAd4. There are 5 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 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.1672A>G	p.Ile558Val	missense	Exon 10 of 14	NP_009009.1	O75112-1
	LDB3	NM_001171610.2		c.1687A>G	p.Ile563Val	missense	Exon 10 of 14	NP_001165081.1	O75112-7
	LDB3	NM_001368066.1		c.1531A>G	p.Ile511Val	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.1672A>G	p.Ile558Val	missense	Exon 10 of 14	ENSP00000355296.3	O75112-1
	LDB3	ENST00000945680.1		c.1876A>G	p.Ile626Val	missense	Exon 10 of 14	ENSP00000615739.1
	LDB3	ENST00000871464.1		c.1813A>G	p.Ile605Val	missense	Exon 11 of 15	ENSP00000541523.1

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152102 Hom.: 0 Cov.: 31

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: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000281 AC: 66 AN: 234716 AF XY: 0.000377

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000303

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000670

Gnomad OTH exome AF: 0.000173

GnomAD4 exome AF: 0.000167 AC: 242 AN: 1451784 Hom.: 5 Cov.: 36 AF XY: 0.000215 AC XY: 155 AN XY: 721834

African (AFR) AF: 0.00 AC: 0 AN: 33222

American (AMR) AF: 0.0000919 AC: 4 AN: 43530

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25930

East Asian (EAS) AF: 0.00 AC: 0 AN: 39286

South Asian (SAS) AF: 0.00152 AC: 130 AN: 85392

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52208

Middle Eastern (MID) AF: 0.00830 AC: 47 AN: 5666

European-Non Finnish (NFE) AF: 0.0000416 AC: 46 AN: 1106538

Other (OTH) AF: 0.000250 AC: 15 AN: 60012

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152220 Hom.: 0 Cov.: 31 AF XY: 0.0000672 AC XY: 5 AN XY: 74424

African (AFR) AF: 0.00 AC: 0 AN: 41548

American (AMR) AF: 0.00 AC: 0 AN: 15290

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68008

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.0000402 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.000412 AC: 50

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	5	2	not provided (7)
-	-	2	Myofibrillar myopathy 4 (2)
-	-	1	Arrhythmogenic right ventricular cardiomyopathy (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.062	T
MetaSVM	Uncertain	0.75	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		9.1
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.68	N
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.72	P
Vest4		0.76
MVP		0.95
MPC		0.59
ClinPred		0.12	T
GERP RS		4.8
Varity_R		0.22
gMVP		0.35
Mutation Taster		=55/45	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs372331627; hg19: chr10-88476524;