8-144522696-C-T

Variant names:

• chr8-144522696-C-T
• rs781048518
• NM_001024678.4:c.1321G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001024678.4(LRRC24):​c.1321G>A​(p.Glu441Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000257 in 1,595,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: LRRC24 NM_001024678.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.77
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21339574).
• BS2: High AC in GnomAd4 at 5 AD gene.

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.1321G>A	p.Glu441Lys	missense	Exon 5 of 5	NP_001019849.2	Q50LG9
	LRRC14	NM_014665.4	MANE Select	c.*1218C>T		3_prime_UTR	Exon 4 of 4	NP_055480.1	Q15048
	LRRC14	NM_001272036.2		c.*1218C>T		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.1321G>A	p.Glu441Lys	missense	Exon 5 of 5	ENSP00000434849.1	Q50LG9
	LRRC14	ENST00000292524.6	TSL:1 MANE Select	c.*1218C>T		3_prime_UTR	Exon 4 of 4	ENSP00000292524.1	Q15048
	LRRC24	ENST00000533758.1	TSL:5	c.1312G>A	p.Glu438Lys	missense	Exon 5 of 5	ENSP00000435653.1	G3V1D8

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152220 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000104 AC: 22 AN: 210630 AF XY: 0.0000603

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000661

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000190

GnomAD4 exome AF: 0.0000250 AC: 36 AN: 1442676 Hom.: 0 Cov.: 32 AF XY: 0.0000181 AC XY: 13 AN XY: 716654

African (AFR) AF: 0.00 AC: 0 AN: 32236

American (AMR) AF: 0.000584 AC: 25 AN: 42832

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25696

East Asian (EAS) AF: 0.00 AC: 0 AN: 38298

South Asian (SAS) AF: 0.00 AC: 0 AN: 83776

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50696

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5724

European-Non Finnish (NFE) AF: 0.00000725 AC: 8 AN: 1103890

Other (OTH) AF: 0.0000504 AC: 3 AN: 59528

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152328 Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4 AN XY: 74500

African (AFR) AF: 0.0000240 AC: 1 AN: 41582

American (AMR) AF: 0.000196 AC: 3 AN: 15308

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000680 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.0000922 AC: 11

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0073	T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	0.70	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		1.8
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.25
Sift	Uncertain	0.024	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.41
MutPred		0.47		Gain of MoRF binding (P = 0.0168)
MVP		0.86
MPC		1.1
ClinPred		0.72	D
GERP RS		4.9
Varity_R		0.23
gMVP		0.56
Mutation Taster		=67/33	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs781048518; hg19: chr8-145748080;