NM_152329.4:c.574C>T

Variant names:

• chr14-49607691-C-T
• NM_152329.4:c.574C>T

Variant summary

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

The NM_152329.4(LRR1):​c.574C>T​(p.Leu192Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LRR1 NM_152329.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.97

Genes affected

LRR1 (HGNC:19742): (leucine rich repeat protein 1) The protein encoded by this gene contains a leucine-rich repeat (LRR). It specifically interacts with TNFRSF9/4-1BB, a member of the tumor necrosis factor receptor (TNFR) superfamily. Overexpression of this gene suppresses the activation of NF-kappa B induced by TNFRSF9 or TNF receptor-associated factor 2 (TRAF2), which suggests that this protein is a negative regulator of TNFRSF9-mediated signaling cascades. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Feb 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRR1	NM_152329.4	c.574C>T	p.Leu192Phe	missense_variant	Exon 3 of 4	ENST00000298288.11	NP_689542.2
LRR1	NM_203467.2	c.282+5223C>T		intron_variant	Intron 2 of 2		NP_982292.1
LRR1	NR_037792.2	n.722C>T		non_coding_transcript_exon_variant	Exon 4 of 6
LRR1	NR_037793.2	n.763C>T		non_coding_transcript_exon_variant	Exon 4 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRR1	ENST00000298288.11	c.574C>T	p.Leu192Phe	missense_variant	Exon 3 of 4	1	NM_152329.4	ENSP00000298288.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 18, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.574C>T (p.L192F) alteration is located in exon 3 (coding exon 3) of the LRR1 gene. This alteration results from a C to T substitution at nucleotide position 574, causing the leucine (L) at amino acid position 192 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	Benign	0.31
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.079	T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.027	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.19
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.78
MutPred		0.53		Gain of catalytic residue at A194 (P = 0.001);
MVP		0.85
MPC		0.62
ClinPred		0.95	D
GERP RS		5.7
Varity_R		0.42
gMVP		0.61

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-50074409;