8-144520748-G-A

Variant summary

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

The NM_014665.4(LRRC14):c.840G>A(p.Met280Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: LRRC14 NM_014665.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.815

Genes affected

LRRC14 (HGNC:20419): (leucine rich repeat containing 14) This gene encodes a leucine-rich repeat-containing protein. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Dec 2012]

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=0.118071735).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRC14	NM_014665.4	c.840G>A	p.Met280Ile	missense_variant	3/4	ENST00000292524.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRC14	ENST00000292524.6	c.840G>A	p.Met280Ile	missense_variant	3/4	1	NM_014665.4	P1
LRRC14	ENST00000529022.5	c.840G>A	p.Met280Ile	missense_variant	4/5	1		P1
LRRC14	ENST00000527730.1	c.840G>A	p.Met280Ile	missense_variant	3/3	2
LRRC14	ENST00000531310.1	n.1295G>A		non_coding_transcript_exon_variant	2/2	5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 34

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

Nov 02, 2023

The c.840G>A (p.M280I) alteration is located in exon 3 (coding exon 2) of the LRRC14 gene. This alteration results from a G to A substitution at nucleotide position 840, causing the methionine (M) at amino acid position 280 to be replaced by an isoleucine (I). 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	0.56
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	21
Dann	Benign	0.97
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.81	T;.;T
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.92	D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.48	N;N;N
REVEL	Benign	0.096
Sift	Benign	0.15	T;T;T
Sift4G	Benign	0.40	T;T;T
Polyphen		0.0040	.;B;B
Vest4		0.31, 0.31
MutPred		0.50		Loss of disorder (P = 0.0781);Loss of disorder (P = 0.0781);Loss of disorder (P = 0.0781);
MVP		0.35
MPC		0.49
ClinPred		0.24	T
GERP RS		3.5
Varity_R		0.10
gMVP		0.55

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-145746132;