11-540740-G-A

Position:

• chr11-540740-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_198075.4(LRRC56):​c.56G>A​(p.Arg19Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00176 in 1,612,038 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R19W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0037 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (17 hom.)
• Consequence: LRRC56 NM_198075.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.92

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004208058).
• BP6: Variant 11-540740-G-A is Benign according to our data. Variant chr11-540740-G-A is described in ClinVar as [Benign]. Clinvar id is 1618879.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00365 (556/152224) while in subpopulation AFR AF= 0.00883 (367/41562). AF 95% confidence interval is 0.00809. There are 1 homozygotes in gnomad4. There are 264 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRC56	NM_198075.4	c.56G>A	p.Arg19Gln	missense_variant	4/14	ENST00000270115.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRC56	ENST00000270115.8	c.56G>A	p.Arg19Gln	missense_variant	4/14	1	NM_198075.4	P1

Frequencies

GnomAD3 genomes AF: 0.00366 AC: 556 AN: 152106 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00886

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00374

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00146

Gnomad OTH AF: 0.00479

GnomAD3 exomes AF: 0.00205 AC: 506 AN: 246454 Hom.: 3 AF XY: 0.00206 AC XY: 276 AN XY: 133666

Gnomad AFR exome AF: 0.00851

Gnomad AMR exome AF: 0.00239

Gnomad ASJ exome AF: 0.00101

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00119

Gnomad FIN exome AF: 0.0000491

Gnomad NFE exome AF: 0.00196

Gnomad OTH exome AF: 0.00382

GnomAD4 exome AF: 0.00157 AC: 2287 AN: 1459814 Hom.: 17 Cov.: 32 AF XY: 0.00161 AC XY: 1167 AN XY: 726092

Gnomad4 AFR exome AF: 0.00968

Gnomad4 AMR exome AF: 0.00273

Gnomad4 ASJ exome AF: 0.000729

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00110

Gnomad4 FIN exome AF: 0.0000958

Gnomad4 NFE exome AF: 0.00126

Gnomad4 OTH exome AF: 0.00328

GnomAD4 genome AF: 0.00365 AC: 556 AN: 152224 Hom.: 1 Cov.: 32 AF XY: 0.00355 AC XY: 264 AN XY: 74434

Gnomad4 AFR AF: 0.00883

Gnomad4 AMR AF: 0.00373

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00331

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00146

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.00241 Hom.: 3

Bravo AF: 0.00393

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00726 AC: 32

ESP6500EA AF: 0.00198 AC: 17

ExAC AF: 0.00223 AC: 270

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00267

EpiControl AF: 0.00310

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

LRRC56-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 22, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.078
DANN	Benign	0.88
DEOGEN2	Benign	0.0027	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0072	N
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.52	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.76	N
REVEL	Benign	0.011
Sift	Benign	0.35	T
Sift4G	Benign	0.28	T
Polyphen		0.018	B
Vest4		0.050
MVP		0.13
ClinPred		0.0033	T
GERP RS		-5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.037
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs144525570; hg19: chr11-540740;