10-86666837-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001368064.1(LDB3):c.-35G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000694 in 469,870 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0018 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: LDB3 NM_001368064.1 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.143

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030962229).
• BP6: Variant 10-86666837-G-T is Benign according to our data. Variant chr10-86666837-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 2640653.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0018 (273/151374) while in subpopulation AFR AF= 0.00642 (265/41284). AF 95% confidence interval is 0.00578. There are 2 homozygotes in gnomad4. There are 132 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 273 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDB3	NM_001368063.1	c.-35G>T		5_prime_UTR_variant	1/8
LDB3	NM_001368064.1	c.-35G>T		5_prime_UTR_variant	1/13
LDB3	NM_001368068.1	c.-35G>T		5_prime_UTR_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDB3	ENST00000688001.1	c.-35G>T		5_prime_UTR_variant	1/13			A2
LDB3	ENST00000688785.1	c.-35G>T		5_prime_UTR_variant	1/8
LDB3	ENST00000691462.1	c.-35G>T		5_prime_UTR_variant	1/8
LDB3	ENST00000687856.1	c.-35G>T		5_prime_UTR_variant, NMD_transcript_variant	1/6

Frequencies

GnomAD3 genomes AF: 0.00180 AC: 273 AN: 151252 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00644

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000397

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: 0.000963

GnomAD3 exomes AF: 0.000305 AC: 45 AN: 147742 Hom.: 0 AF XY: 0.000239 AC XY: 19 AN XY: 79616

Gnomad AFR exome AF: 0.00586

Gnomad AMR exome AF: 0.0000816

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: 0.0000365

Gnomad OTH exome AF: 0.000233

GnomAD4 exome AF: 0.000166 AC: 53 AN: 318496 Hom.: 0 Cov.: 0 AF XY: 0.000117 AC XY: 21 AN XY: 179986

Gnomad4 AFR exome AF: 0.00487

Gnomad4 AMR exome AF: 0.0000733

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000335

Gnomad4 FIN exome AF: 0.0000373

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.000140

GnomAD4 genome AF: 0.00180 AC: 273 AN: 151374 Hom.: 2 Cov.: 33 AF XY: 0.00179 AC XY: 132 AN XY: 73924

Gnomad4 AFR AF: 0.00642

Gnomad4 AMR AF: 0.000397

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000952

Alfa AF: 0.000820 Hom.: 0

Bravo AF: 0.00233

ExAC AF: 0.000284 AC: 9

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2023

LDB3: BS1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	13
Dann	Uncertain	0.98
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N
PROVEAN	Benign	0.60	N
REVEL	Benign	0.071
Sift	Benign	0.19	T
Sift4G	Benign	0.17	T
Polyphen		0.0	B
MVP		0.19
ClinPred		0.0080	T
GERP RS		1.6

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs550972381; hg19: chr10-88426594;