11-540719-G-A

Position:

• chr11-540719-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.35G>A​(p.Arg12Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00363 in 1,612,636 control chromosomes in the GnomAD database, including 94 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0055 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (85 hom.)
• Consequence: LRRC56 NM_198075.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.174

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=0.002892375).
• BP6: Variant 11-540719-G-A is Benign according to our data. Variant chr11-540719-G-A is described in ClinVar as [Benign]. Clinvar id is 1598826.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00548 (835/152302) while in subpopulation EAS AF= 0.021 (109/5180). AF 95% confidence interval is 0.0178. There are 9 homozygotes in gnomad4. There are 525 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRRC56	NM_198075.4	c.35G>A	p.Arg12Gln	missense_variant	4/14	ENST00000270115.8	NP_932341.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRRC56	ENST00000270115.8	c.35G>A	p.Arg12Gln	missense_variant	4/14	1	NM_198075.4	ENSP00000270115.7

Frequencies

GnomAD3 genomes AF: 0.00549 AC: 836 AN: 152184 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0156

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.0212

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0317

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000720

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.0104 AC: 2577 AN: 247974 Hom.: 46 AF XY: 0.00884 AC XY: 1188 AN XY: 134464

Gnomad AFR exome AF: 0.00119

Gnomad AMR exome AF: 0.0369

Gnomad ASJ exome AF: 0.00351

Gnomad EAS exome AF: 0.0195

Gnomad SAS exome AF: 0.00171

Gnomad FIN exome AF: 0.0329

Gnomad NFE exome AF: 0.00112

Gnomad OTH exome AF: 0.00693

GnomAD4 exome AF: 0.00343 AC: 5015 AN: 1460334 Hom.: 85 Cov.: 32 AF XY: 0.00330 AC XY: 2396 AN XY: 726406

Gnomad4 AFR exome AF: 0.00105

Gnomad4 AMR exome AF: 0.0358

Gnomad4 ASJ exome AF: 0.00353

Gnomad4 EAS exome AF: 0.0244

Gnomad4 SAS exome AF: 0.00178

Gnomad4 FIN exome AF: 0.0303

Gnomad4 NFE exome AF: 0.000335

Gnomad4 OTH exome AF: 0.00336

GnomAD4 genome AF: 0.00548 AC: 835 AN: 152302 Hom.: 9 Cov.: 32 AF XY: 0.00705 AC XY: 525 AN XY: 74446

Gnomad4 AFR AF: 0.00130

Gnomad4 AMR AF: 0.0156

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.0210

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.0317

Gnomad4 NFE AF: 0.000720

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00277 Hom.: 11

Bravo AF: 0.00512

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.00867 AC: 1052

Asia WGS AF: 0.0140 AC: 48 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000416

ClinVar

Significance: Benign

Submissions summary: Benign:4

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 29, 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

May 17, 2024

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). -

Ciliary dyskinesia, primary, 39 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 07, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	12
DANN	Uncertain	1.0
DEOGEN2	Benign	0.033	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.087	N
LIST_S2	Benign	0.55	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.028
Sift	Benign	0.097	T
Sift4G	Uncertain	0.057	T
Polyphen		0.44	B
Vest4		0.14
ClinPred		0.017	T
GERP RS		3.0
Varity_R		0.055
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2277269; hg19: chr11-540719;