21-44456778-C-T

Variant names:

• chr21-44456778-C-T
• rs2051704533
• NM_030891.6:c.134C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_030891.6(LRRC3):​c.134C>T​(p.Ala45Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LRRC3 NM_030891.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0620

Genes affected

LRRC3 (HGNC:14965): (leucine rich repeat containing 3) Predicted to be integral component of membrane. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12787732).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRC3	NM_030891.6	c.134C>T	p.Ala45Val	missense_variant	Exon 2 of 2	ENST00000291592.6	NP_112153.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRRC3	ENST00000291592.6	c.134C>T	p.Ala45Val	missense_variant	Exon 2 of 2	1	NM_030891.6	ENSP00000291592.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458824 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 2 AN XY: 725878

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 27, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.134C>T (p.A45V) alteration is located in exon 2 (coding exon 1) of the LRRC3 gene. This alteration results from a C to T substitution at nucleotide position 134, causing the alanine (A) at amino acid position 45 to be replaced by a valine (V). 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	Benign	0.14
BayesDel_addAF	Benign	-0.061	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	9.0
DANN	Benign	0.72
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.13	T
MetaSVM	Uncertain	-0.081	T
MutationAssessor	Benign	0.86	L
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.24
Sift	Benign	0.54	T
Sift4G	Benign	0.61	T
Polyphen		0.0020	B
Vest4		0.052
MutPred		0.71		Gain of sheet (P = 0.1208);
MVP		0.91
MPC		0.26
ClinPred		0.073	T
GERP RS		2.0
Varity_R		0.070
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs2051704533; hg19: chr21-45876661;