11-540736-G-T

Variant names:

• chr11-540736-G-T
• rs772525350
• NM_198075.4:c.52G>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_198075.4(LRRC56):​c.52G>T​(p.Val18Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000633 in 1,612,314 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V18I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000058 (0 hom.)
• Consequence: LRRC56 NM_198075.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.50

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

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.060904652).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000118 (18/152304) while in subpopulation AMR AF = 0.000915 (14/15302). AF 95% confidence interval is 0.000553. There are 0 homozygotes in GnomAd4. There are 11 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRC56	NM_198075.4	c.52G>T	p.Val18Phe	missense_variant	Exon 4 of 14	ENST00000270115.8	NP_932341.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRRC56	ENST00000270115.8	c.52G>T	p.Val18Phe	missense_variant	Exon 4 of 14	1	NM_198075.4	ENSP00000270115.7

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000890 AC: 22 AN: 247118 AF XY: 0.0000821

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000408

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000626

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000575 AC: 84 AN: 1460010 Hom.: 0 Cov.: 32 AF XY: 0.0000606 AC XY: 44 AN XY: 726196

Gnomad4 AFR exome AF: 0.0000299 AC: 1 AN: 33472

Gnomad4 AMR exome AF: 0.000448 AC: 20 AN: 44638

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26086

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39690

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86038

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 52244

Gnomad4 NFE exome AF: 0.0000432 AC: 48 AN: 1111768

Gnomad4 Remaining exome AF: 0.000199 AC: 12 AN: 60336

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152304 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74466

Gnomad4 AFR AF: 0.0000241 AC: 0.0000240662 AN: 0.0000240662

Gnomad4 AMR AF: 0.000915 AC: 0.000914913 AN: 0.000914913

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000147 AC: 0.000014702 AN: 0.000014702

Gnomad4 OTH AF: 0.000473 AC: 0.000473485 AN: 0.000473485

Alfa AF: 0.0000768 Hom.: 0

Bravo AF: 0.000306

ExAC AF: 0.0000990 AC: 12

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

May 25, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 18 of the LRRC56 protein (p.Val18Phe). This variant is present in population databases (rs772525350, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with LRRC56-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The phenylalanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.57
DANN	Benign	0.77
DEOGEN2	Benign	0.010	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.061	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.049
Sift	Benign	0.14	T
Sift4G	Uncertain	0.036	D
Polyphen		0.99	D
Vest4		0.18
MutPred		0.47		Loss of sheet (P = 0.0315);
MVP		0.12
ClinPred		0.080	T
GERP RS		-2.5
Varity_R		0.063
gMVP		0.66
Mutation Taster		=94/6	polymorphism

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: rs772525350; hg19: chr11-540736;