14-49599177-A-C

Variant names:

• chr14-49599177-A-C
• rs1881935918
• NM_152329.4:c.157A>C

Variant summary

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

The NM_152329.4(LRR1):​c.157A>C​(p.Lys53Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,310 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: LRR1 NM_152329.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.02

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]

RPS29 (HGNC:10419): (ribosomal protein S29) Ribosomes, the organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are composed of 4 RNA species and approximately 80 structurally distinct proteins. This gene encodes a ribosomal protein that is a component of the 40S subunit and a member of the S14P family of ribosomal proteins. The protein, which contains a C2-C2 zinc finger-like domain that can bind to zinc, can enhance the tumor suppressor activity of Ras-related protein 1A (KREV1). It is located in the cytoplasm. Variable expression of this gene in colorectal cancers compared to adjacent normal tissues has been observed, although no correlation between the level of expression and the severity of the disease has been found. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2013]

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=0.29543653).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRR1	NM_152329.4	c.157A>C	p.Lys53Gln	missense_variant	Exon 1 of 4	ENST00000298288.11	NP_689542.2
LRR1	NM_203467.2	c.157A>C	p.Lys53Gln	missense_variant	Exon 1 of 3		NP_982292.1
LRR1	NR_037792.2	n.238A>C		non_coding_transcript_exon_variant	Exon 1 of 6
LRR1	NR_037793.2	n.238A>C		non_coding_transcript_exon_variant	Exon 1 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRR1	ENST00000298288.11	c.157A>C	p.Lys53Gln	missense_variant	Exon 1 of 4	1	NM_152329.4	ENSP00000298288.6

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456310 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 723814

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.157A>C (p.K53Q) alteration is located in exon 1 (coding exon 1) of the LRR1 gene. This alteration results from a A to C substitution at nucleotide position 157, causing the lysine (K) at amino acid position 53 to be replaced by a glutamine (Q). 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	0.18
BayesDel_addAF	Benign	-0.085	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0039	T;.
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.85	D;D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.30	T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.7	L;L
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.13
Sift	Uncertain	0.029	D;T
Sift4G	Benign	0.11	T;D
Polyphen		0.88	P;D
Vest4		0.34
MutPred		0.41		Loss of loop (P = 0.0374);Loss of loop (P = 0.0374);
MVP		0.80
MPC		0.28
ClinPred		0.87	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.30
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1881935918; hg19: chr14-50065895;