10-86706679-T-G

Variant names:

• chr10-86706679-T-G
• rs147042608
• NM_007078.3:c.1045T>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_007078.3(LDB3):​c.1045T>G​(p.Ser349Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/21 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. S349T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LDB3 NM_007078.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0940
• Publications: 0 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 -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0625349).
• BP6: Variant 10-86706679-T-G is Benign according to our data. Variant chr10-86706679-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1775364.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1045T>G	p.Ser349Ala	missense	Exon 8 of 14	NP_009009.1	O75112-1
	LDB3	NM_001368066.1		c.904T>G	p.Ser302Ala	missense	Exon 9 of 15	NP_001354995.1	A0A8I5KV04
	LDB3	NM_001171610.2		c.1101-3226T>G		intron	N/A	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.1045T>G	p.Ser349Ala	missense	Exon 8 of 14	ENSP00000355296.3	O75112-1
	LDB3	ENST00000945680.1		c.1249T>G	p.Ser417Ala	missense	Exon 8 of 14	ENSP00000615739.1
	LDB3	ENST00000871464.1		c.1045T>G	p.Ser349Ala	missense	Exon 8 of 15	ENSP00000541523.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.54
DANN	Benign	0.19
DEOGEN2	Benign	0.22	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.0095	N
LIST_S2	Benign	0.18	T
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.063	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.65	N
PhyloP100		-0.094
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.49	N
REVEL	Benign	0.060
Sift	Benign	0.42	T
Sift4G	Benign	0.66	T
Polyphen		0.14	B
Vest4		0.096
MutPred		0.28		Loss of glycosylation at S349 (P = 5e-04)
MVP		0.35
ClinPred		0.085	T
GERP RS		-0.47
Varity_R		0.060
Mutation Taster		=95/5	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: rs147042608; hg19: chr10-88466436;