chr11-540736-GTCC-G

Position:

• chr11-540736-GTCC-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PM4_Supporting BS1_Supporting

The NM_198075.4(LRRC56):​c.53_55del​(p.Val18_Arg19delinsGly) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.000311 in 1,612,196 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00032 (0 hom.)
• Consequence: LRRC56 NM_198075.4 inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.08

Genes affected

LRRC56 (HGNC:25430): (leucine rich repeat containing 56) Predicted to be involved in cell projection organization. Predicted to be located in cilium. Implicated in primary ciliary dyskinesia 39. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_198075.4. Strenght limited to Supporting due to length of the change: 1aa.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00021 (32/152186) while in subpopulation AMR AF= 0.000785 (12/15282). AF 95% confidence interval is 0.000452. There are 0 homozygotes in gnomad4. There are 13 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRC56	NM_198075.4	c.53_55del	p.Val18_Arg19delinsGly	inframe_deletion	4/14	ENST00000270115.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRC56	ENST00000270115.8	c.53_55del	p.Val18_Arg19delinsGly	inframe_deletion	4/14	1	NM_198075.4	P1

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

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: 0.000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000214 AC: 53 AN: 247118 Hom.: 0 AF XY: 0.000216 AC XY: 29 AN XY: 134014

Gnomad AFR exome AF: 0.0000629

Gnomad AMR exome AF: 0.000204

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000330

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000375

Gnomad OTH exome AF: 0.000332

GnomAD4 exome AF: 0.000322 AC: 470 AN: 1460010 Hom.: 0 AF XY: 0.000310 AC XY: 225 AN XY: 726194

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000224

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: 0.000401

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74338

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000785

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000347 Hom.: 0

Bravo AF: 0.000302

EpiCase AF: 0.000545

EpiControl AF: 0.000713

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ciliary dyskinesia, primary, 39 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetics and Molecular Pathology, SA Pathology

Jun 02, 2023

The LRRC56 c.53_55del variant is classified as a VUS (PM4) The LRRC56 c.53_55del variant results in an inframe deletion in exon 4/14. It is predicted to alter the length of the protein produced by this gene due to an inframe deletion variant in a nonrepeat region (PM4). The variant is rare in population databases (gnomAD allele frequency = 0.021%; 32 het and 0 hom in 152,186 sequenced alleles). The variant has been reported in dbSNP (rs759014538) and has been reported as Uncertain significance by other diagnostic laboratories (ClinVar Variation ID: 1523693). It has not been reported in HGMD (2023.1) or the scientific literature to date. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 15, 2022

This variant, c.53_55del, is a complex sequence change that results in the deletion of 2 and insertion of 1 amino acid(s) in the LRRC56 protein (p.Val18_Arg19delinsGly). This variant is present in population databases (rs759014538, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with LRRC56-related conditions. ClinVar contains an entry for this variant (Variation ID: 1523693). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs759014538; hg19: chr11-540736;