NM_007078.3:c.1422G>A

Variant names:

• chr10-86716517-G-A
• rs142625982
• NM_007078.3:c.1422G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_007078.3(LDB3):​c.1422G>A​(p.Ser474Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00235 in 1,610,926 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 30)
  • Exomes 𝑓: 0.0024 (7 hom.)
• Consequence: LDB3 NM_007078.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -1.40
• Publications: 5 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 -16 ACMG points.

• BP6: Variant 10-86716517-G-A is Benign according to our data. Variant chr10-86716517-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 36444.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00139 (208/149260) while in subpopulation NFE AF = 0.00221 (149/67360). AF 95% confidence interval is 0.00192. There are 1 homozygotes in GnomAd4. There are 92 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 7 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.1422G>A	p.Ser474Ser	synonymous	Exon 10 of 14	NP_009009.1	O75112-1
	LDB3	NM_001171610.2		c.1437G>A	p.Ser479Ser	synonymous	Exon 10 of 14	NP_001165081.1	O75112-7
	LDB3	NM_001368066.1		c.1281G>A	p.Ser427Ser	synonymous	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.1422G>A	p.Ser474Ser	synonymous	Exon 10 of 14	ENSP00000355296.3	O75112-1
	LDB3	ENST00000945680.1		c.1626G>A	p.Ser542Ser	synonymous	Exon 10 of 14	ENSP00000615739.1
	LDB3	ENST00000871464.1		c.1563G>A	p.Ser521Ser	synonymous	Exon 11 of 15	ENSP00000541523.1

Frequencies

GnomAD3 genomes AF: 0.00139 AC: 208 AN: 149148 Hom.: 1 Cov.: 30

Gnomad AFR AF: 0.000695

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000403

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000200

Gnomad SAS AF: 0.000430

Gnomad FIN AF: 0.00206

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00221

Gnomad OTH AF: 0.000486

GnomAD2 exomes AF: 0.00107 AC: 266 AN: 248768 AF XY: 0.00103

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.000878

Gnomad NFE exome AF: 0.00181

Gnomad OTH exome AF: 0.000980

GnomAD4 exome AF: 0.00245 AC: 3581 AN: 1461666 Hom.: 7 Cov.: 36 AF XY: 0.00236 AC XY: 1713 AN XY: 727102

African (AFR) AF: 0.000418 AC: 14 AN: 33476

American (AMR) AF: 0.000335 AC: 15 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26120

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39686

South Asian (SAS) AF: 0.000672 AC: 58 AN: 86252

European-Finnish (FIN) AF: 0.000618 AC: 33 AN: 53390

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5762

European-Non Finnish (NFE) AF: 0.00296 AC: 3295 AN: 1111884

Other (OTH) AF: 0.00268 AC: 162 AN: 60378

GnomAD4 genome AF: 0.00139 AC: 208 AN: 149260 Hom.: 1 Cov.: 30 AF XY: 0.00127 AC XY: 92 AN XY: 72622

African (AFR) AF: 0.000693 AC: 28 AN: 40428

American (AMR) AF: 0.000403 AC: 6 AN: 14892

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.000200 AC: 1 AN: 4994

South Asian (SAS) AF: 0.000431 AC: 2 AN: 4642

European-Finnish (FIN) AF: 0.00206 AC: 21 AN: 10210

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00221 AC: 149 AN: 67360

Other (OTH) AF: 0.000481 AC: 1 AN: 2080

Alfa AF: 0.00177 Hom.: 0

Bravo AF: 0.00120

EpiCase AF: 0.00262

EpiControl AF: 0.00213

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	5	not specified (5)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Myofibrillar myopathy 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	4.7
DANN	Benign	0.34
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.46		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.46		Position offset: 2

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

Other links and lift over

dbSNP: rs142625982; hg19: chr10-88476274;