NM_007078.3:c.1312A>G

Variant names:

• chr10-86716407-A-G
• rs111941389
• NM_007078.3:c.1312A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_007078.3(LDB3):​c.1312A>G​(p.Thr438Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 894,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T438N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00050 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: LDB3 NM_007078.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 1.91
• Publications: 3 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.020117491).
• BP6: Variant 10-86716407-A-G is Benign according to our data. Variant chr10-86716407-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 568889.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000501 (12/23968) while in subpopulation AFR AF = 0.0019 (12/6326). AF 95% confidence interval is 0.00109. There are 0 homozygotes in GnomAd4. There are 6 alleles in the male GnomAd4 subpopulation. Median coverage is 0. 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.1312A>G	p.Thr438Ala	missense	Exon 10 of 14	NP_009009.1	O75112-1
	LDB3	NM_001171610.2		c.1327A>G	p.Thr443Ala	missense	Exon 10 of 14	NP_001165081.1	O75112-7
	LDB3	NM_001368066.1		c.1171A>G	p.Thr391Ala	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.1312A>G	p.Thr438Ala	missense	Exon 10 of 14	ENSP00000355296.3	O75112-1
	LDB3	ENST00000945680.1		c.1516A>G	p.Thr506Ala	missense	Exon 10 of 14	ENSP00000615739.1
	LDB3	ENST00000871464.1		c.1453A>G	p.Thr485Ala	missense	Exon 11 of 15	ENSP00000541523.1

Frequencies

GnomAD3 genomes AF: 0.000459 AC: 11 AN: 23946 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00174

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000472 AC: 6 AN: 127082 AF XY: 0.0000288

Gnomad AFR exome AF: 0.000839

Gnomad AMR exome AF: 0.0000546

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: 0.0000207 AC: 18 AN: 870870 Hom.: 0 Cov.: 34 AF XY: 0.0000256 AC XY: 11 AN XY: 429426

African (AFR) AF: 0.000560 AC: 11 AN: 19650

American (AMR) AF: 0.0000407 AC: 1 AN: 24540

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12746

East Asian (EAS) AF: 0.00 AC: 0 AN: 10576

South Asian (SAS) AF: 0.00 AC: 0 AN: 50890

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22164

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2096

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 697200

Other (OTH) AF: 0.000193 AC: 6 AN: 31008

GnomAD4 genome AF: 0.000501 AC: 12 AN: 23968 Hom.: 0 Cov.: 0 AF XY: 0.000508 AC XY: 6 AN XY: 11812

African (AFR) AF: 0.00190 AC: 12 AN: 6326

American (AMR) AF: 0.00 AC: 0 AN: 2340

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 600

East Asian (EAS) AF: 0.00 AC: 0 AN: 676

South Asian (SAS) AF: 0.00 AC: 0 AN: 484

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1324

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 40

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 11658

Other (OTH) AF: 0.00 AC: 0 AN: 336

Alfa AF: 0.000253 Hom.: 0

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000344 AC: 4

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	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	0.086
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	11
DANN	Benign	0.90
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.36	N
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.020	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L
PhyloP100		1.9
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.047
Sift	Benign	0.16	T
Sift4G	Benign	0.60	T
Polyphen		0.0020	B
Vest4		0.22
MVP		0.60
MPC		0.19
ClinPred		0.025	T
GERP RS		3.4
Varity_R		0.085
gMVP		0.30
Mutation Taster		=90/10	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: rs111941389; hg19: chr10-88476164;