16-67375346-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_018296.6(LRRC36):c.1594C>T(p.Leu532Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000754 in 1,459,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: LRRC36 NM_018296.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.87

Genes affected

LRRC36 (HGNC:25615): (leucine rich repeat containing 36)

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3296232).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRC36	NM_018296.6	c.1594C>T	p.Leu532Phe	missense_variant	10/14	ENST00000329956.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRC36	ENST00000329956.11	c.1594C>T	p.Leu532Phe	missense_variant	10/14	1	NM_018296.6	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000804 AC: 2 AN: 248798 Hom.: 0 AF XY: 0.00000743 AC XY: 1 AN XY: 134548

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000661

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000754 AC: 11 AN: 1459648 Hom.: 0 Cov.: 33 AF XY: 0.00000964 AC XY: 7 AN XY: 726156

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000698

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 14, 2023

The c.1594C>T (p.L532F) alteration is located in exon 10 (coding exon 10) of the LRRC36 gene. This alteration results from a C to T substitution at nucleotide position 1594, causing the leucine (L) at amino acid position 532 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.36
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.012	T;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.33	T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	1.5	L;.
MutationTaster	Benign	0.55	D;D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.083
Sift	Benign	0.091	T;T
Sift4G	Benign	0.25	T;T
Polyphen		0.70	P;D
Vest4		0.59
MutPred		0.25		Gain of catalytic residue at L532 (P = 0.234);.;
MVP		0.48
MPC		0.85
ClinPred		0.90	D
GERP RS		4.7
Varity_R		0.13
gMVP		0.35

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: rs749805396; hg19: chr16-67409249;