8-144522713-G-T

Position:

• chr8-144522713-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001024678.4(LRRC24):​c.1304C>A​(p.Ala435Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000762 in 1,442,968 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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: 0.0000076 (0 hom.)
• Consequence: LRRC24 NM_001024678.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.164

Genes affected

LRRC24 (HGNC:28947): (leucine rich repeat containing 24) Predicted to act upstream of or within positive regulation of synapse assembly. Predicted to be integral component of membrane. Predicted to be active in extracellular matrix and extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04996085).
• BS2: High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRRC24	NM_001024678.4	c.1304C>A	p.Ala435Glu	missense_variant	5/5	ENST00000529415.7	NP_001019849.2
LRRC14	NM_014665.4	c.*1235G>T		3_prime_UTR_variant	4/4	ENST00000292524.6	NP_055480.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRRC24	ENST00000529415.7	c.1304C>A	p.Ala435Glu	missense_variant	5/5	1	NM_001024678.4	ENSP00000434849.1
LRRC14	ENST00000292524.6	c.*1235G>T		3_prime_UTR_variant	4/4	1	NM_014665.4	ENSP00000292524.1
LRRC24	ENST00000533758.1	c.1295C>A	p.Ala432Glu	missense_variant	5/5	5		ENSP00000435653.1
LRRC14	ENST00000528528.1	n.132G>T		non_coding_transcript_exon_variant	1/3	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000762 AC: 11 AN: 1442968 Hom.: 0 Cov.: 32 AF XY: 0.0000126 AC XY: 9 AN XY: 716802

Gnomad4 AFR exome AF: 0.0000929

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000119

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000101

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000151

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

Aug 25, 2024

The c.1304C>A (p.A435E) alteration is located in exon 5 (coding exon 4) of the LRRC24 gene. This alteration results from a C to A substitution at nucleotide position 1304, causing the alanine (A) at amino acid position 435 to be replaced by a glutamic acid (E). 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	0.074
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	11
DANN	Benign	0.67
DEOGEN2	Benign	0.0063	T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.48	T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.050	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;.
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.056
Sift	Benign	1.0	T;T
Sift4G	Benign	0.45	T;T
Polyphen		0.060	B;B
Vest4		0.32
MutPred		0.30		Gain of solvent accessibility (P = 0.0246);.;
MVP		0.56
MPC		0.38
ClinPred		0.067	T
GERP RS		-3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.074
gMVP		0.30

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: rs534786173; hg19: chr8-145748097;