8-144520573-T-C

Position:

• chr8-144520573-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_014665.4(LRRC14):​c.665T>C​(p.Leu222Pro) 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 pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 34)
• Consequence: LRRC14 NM_014665.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.11

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]

LRRC14 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.924

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRRC14	NM_014665.4	c.665T>C	p.Leu222Pro	missense_variant	3/4	ENST00000292524.6	NP_055480.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRRC14	ENST00000292524.6	c.665T>C	p.Leu222Pro	missense_variant	3/4	1	NM_014665.4	ENSP00000292524.1
LRRC14	ENST00000529022.5	c.665T>C	p.Leu222Pro	missense_variant	4/5	1		ENSP00000434768.1
LRRC14	ENST00000527730.1	c.665T>C	p.Leu222Pro	missense_variant	3/3	2		ENSP00000436452.1
LRRC14	ENST00000531310.1	n.1120T>C		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 25, 2024

The c.665T>C (p.L222P) alteration is located in exon 3 (coding exon 2) of the LRRC14 gene. This alteration results from a T to C substitution at nucleotide position 665, causing the leucine (L) at amino acid position 222 to be replaced by a proline (P). 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	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	.;T;T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.74	T;.;T
M_CAP	Uncertain	0.099	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Benign	-0.32	T
MutationAssessor	Uncertain	2.0	.;M;M
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-4.6	D;D;D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0090	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.95, 0.95
MutPred		0.80		Loss of stability (P = 0.0561);Loss of stability (P = 0.0561);Loss of stability (P = 0.0561);
MVP		0.81
MPC		1.7
ClinPred		0.98	D
GERP RS		4.2
Varity_R		0.68
gMVP		0.92

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: rs1586847499; hg19: chr8-145745957;