NM_007078.3:c.-36A>G

Variant names:

• chr10-86668558-A-G
• rs2803557
• NM_007078.3:c.-36A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_007078.3(LDB3):​c.-36A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0136 in 767,794 control chromosomes in the GnomAD database, including 120 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (23 hom., cov: 34)
  • Exomes 𝑓: 0.014 (97 hom.)
• Consequence: LDB3 NM_007078.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.07
• Publications: 1 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

ENSG00000289258 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 10-86668558-A-G is Benign according to our data. Variant chr10-86668558-A-G is described in ClinVar as Benign. ClinVar VariationId is 138105.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 = 0.012 (1827/152304) while in subpopulation NFE AF = 0.0192 (1307/68000). AF 95% confidence interval is 0.0184. There are 23 homozygotes in GnomAd4. There are 846 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 23 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.-36A>G		5_prime_UTR	Exon 1 of 14	NP_009009.1	O75112-1
	LDB3	NM_001368067.1	MANE Plus Clinical	c.-36A>G		5_prime_UTR	Exon 1 of 9	NP_001354996.1	A0A0S2Z530
	LDB3	NM_001171610.2		c.-36A>G		5_prime_UTR	Exon 1 of 14	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.-36A>G		5_prime_UTR	Exon 1 of 14	ENSP00000355296.3	O75112-1
	LDB3	ENST00000263066.11	TSL:1 MANE Plus Clinical	c.-36A>G		5_prime_UTR	Exon 1 of 9	ENSP00000263066.7	O75112-6
	ENSG00000289258	ENST00000443292.2	TSL:1	c.1487-111A>G		intron	N/A	ENSP00000393132.2	C9JWU6

Frequencies

GnomAD3 genomes AF: 0.0120 AC: 1827 AN: 152186 Hom.: 23 Cov.: 34

Gnomad AFR AF: 0.00422

Gnomad AMI AF: 0.0362

Gnomad AMR AF: 0.0136

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00320

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0192

Gnomad OTH AF: 0.0115

GnomAD4 exome AF: 0.0141 AC: 8653 AN: 615490 Hom.: 97 Cov.: 7 AF XY: 0.0137 AC XY: 4550 AN XY: 333140

African (AFR) AF: 0.00431 AC: 75 AN: 17384

American (AMR) AF: 0.00900 AC: 347 AN: 38556

Ashkenazi Jewish (ASJ) AF: 0.0180 AC: 370 AN: 20548

East Asian (EAS) AF: 0.0000292 AC: 1 AN: 34220

South Asian (SAS) AF: 0.00195 AC: 130 AN: 66680

European-Finnish (FIN) AF: 0.00442 AC: 183 AN: 41378

Middle Eastern (MID) AF: 0.00479 AC: 20 AN: 4176

European-Non Finnish (NFE) AF: 0.0197 AC: 7074 AN: 359796

Other (OTH) AF: 0.0138 AC: 453 AN: 32752

GnomAD4 genome AF: 0.0120 AC: 1827 AN: 152304 Hom.: 23 Cov.: 34 AF XY: 0.0114 AC XY: 846 AN XY: 74476

African (AFR) AF: 0.00421 AC: 175 AN: 41578

American (AMR) AF: 0.0136 AC: 208 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0112 AC: 39 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4824

European-Finnish (FIN) AF: 0.00320 AC: 34 AN: 10626

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0192 AC: 1307 AN: 68000

Other (OTH) AF: 0.0114 AC: 24 AN: 2114

Alfa AF: 0.0161 Hom.: 8

Bravo AF: 0.0130

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	11
DANN	Benign	0.67
PhyloP100		1.1
PromoterAI		-0.042	Neutral
Mutation Taster		=300/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs2803557; hg19: chr10-88428315; COSMIC: COSV53940137; COSMIC: COSV53940137;