NM_001024678.4:c.1319G>T

Variant names:

• chr8-144522698-C-A
• rs750273850
• NM_001024678.4:c.1319G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001024678.4(LRRC24):​c.1319G>T​(p.Gly440Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000251 in 1,595,766 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G440E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: LRRC24 NM_001024678.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.91
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40389636).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001024678.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRC24	NM_001024678.4	MANE Select	c.1319G>T	p.Gly440Val	missense	Exon 5 of 5	NP_001019849.2	Q50LG9
	LRRC14	NM_014665.4	MANE Select	c.*1220C>A		3_prime_UTR	Exon 4 of 4	NP_055480.1	Q15048
	LRRC14	NM_001272036.2		c.*1220C>A		3_prime_UTR	Exon 5 of 5	NP_001258965.1	Q15048

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRC24	ENST00000529415.7	TSL:1 MANE Select	c.1319G>T	p.Gly440Val	missense	Exon 5 of 5	ENSP00000434849.1	Q50LG9
	LRRC14	ENST00000292524.6	TSL:1 MANE Select	c.*1220C>A		3_prime_UTR	Exon 4 of 4	ENSP00000292524.1	Q15048
	LRRC24	ENST00000533758.1	TSL:5	c.1310G>T	p.Gly437Val	missense	Exon 5 of 5	ENSP00000435653.1	G3V1D8

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000472 AC: 1 AN: 212086 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000108

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000208 AC: 3 AN: 1443550 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 717166

African (AFR) AF: 0.00 AC: 0 AN: 32266

American (AMR) AF: 0.00 AC: 0 AN: 42948

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25716

East Asian (EAS) AF: 0.00 AC: 0 AN: 38316

South Asian (SAS) AF: 0.00 AC: 0 AN: 83882

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50792

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5722

European-Non Finnish (NFE) AF: 0.00000272 AC: 3 AN: 1104348

Other (OTH) AF: 0.00 AC: 0 AN: 59560

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152216 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74372

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41466

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000168 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.065	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.074	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.70	T
M_CAP	Pathogenic	0.76	D
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.9
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.16
Sift	Benign	0.042	D
Sift4G	Benign	0.082	T
Polyphen		0.99	D
Vest4		0.50
MVP		0.46
MPC		1.1
ClinPred		0.45	T
GERP RS		2.9
Varity_R		0.052
gMVP		0.20
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs750273850; hg19: chr8-145748082;