rs201968775

chr10-86706670-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_007078.3(LDB3):c.1036G>A(p.Ala346Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000112 in 1,612,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000068 (0 hom.)
• Consequence: LDB3 NM_007078.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 1.28

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.028349906).
• BP6: Variant 10-86706670-G-A is Benign according to our data. Variant chr10-86706670-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 163845.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000532 (81/152324) while in subpopulation AFR AF= 0.00178 (74/41576). AF 95% confidence interval is 0.00145. There are 0 homozygotes in gnomad4. There are 43 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 75 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDB3	NM_007078.3	c.1036G>A	p.Ala346Thr	missense_variant	8/14	ENST00000361373.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDB3	ENST00000361373.9	c.1036G>A	p.Ala346Thr	missense_variant	8/14	1	NM_007078.3	P4

Frequencies

GnomAD3 genomes AF: 0.000493 AC: 75 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00164

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000846 AC: 21 AN: 248086 Hom.: 0 AF XY: 0.0000890 AC XY: 12 AN XY: 134818

Gnomad AFR exome AF: 0.000753

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000719

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000678 AC: 99 AN: 1460564 Hom.: 0 Cov.: 32 AF XY: 0.0000674 AC XY: 49 AN XY: 726624

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000504

Gnomad4 OTH exome AF: 0.0000663

GnomAD4 genome AF: 0.000532 AC: 81 AN: 152324 Hom.: 0 Cov.: 32 AF XY: 0.000577 AC XY: 43 AN XY: 74498

Gnomad4 AFR AF: 0.00178

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000174 Hom.: 0

Bravo AF: 0.000397

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000907 AC: 11

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 20, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 25, 2022	See Variant Classification Assertion Criteria. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 06, 2017

p.Ala346Thr in exon 10 of LDB3: This variant is not expected to have clinical si gnificance due to frequency in the general population and a lack of conservation across species, including mammals. Of note, 4 non-human primates have a threoni ne (Thr) at this position. In addition, computational prediction tools do not su ggest a high likelihood of impact to the protein. It has also been identified in 0.13% (31/23778) of African chromosomes by the Genome Aggregation Database (gno mAD, http://gnomad.broadinstitute.org; dbSNP rs201968775). ACMG/AMP Criteria app lied: BS1, BP4 (Richards 2015). -

Myofibrillar myopathy 4 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 25, 2023

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 18, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	12
Dann	Benign	0.95
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.0074	T
MetaRNN	Benign	0.028	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.078
Sift	Benign	0.18	T
Sift4G	Benign	0.60	T
Polyphen		0.67	P
Vest4		0.28
MVP		0.55
ClinPred		0.011	T
GERP RS		3.1
Varity_R		0.030

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs201968775; hg19: chr10-88466427; COSMIC: COSV53941462;