8-144522745-C-G

Variant names:

• chr8-144522745-C-G
• rs200595617
• NM_001024678.4:c.1272G>C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001024678.4(LRRC24):​c.1272G>C​(p.Met424Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000606 in 1,587,652 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00064 (1 hom.)
• Consequence: LRRC24 NM_001024678.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.98

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

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.17013398).
• BS2: High AC in GnomAd4 at 43 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRC24	NM_001024678.4	c.1272G>C	p.Met424Ile	missense_variant	Exon 5 of 5	ENST00000529415.7	NP_001019849.2
LRRC14	NM_014665.4	c.*1267C>G		3_prime_UTR_variant	Exon 4 of 4	ENST00000292524.6	NP_055480.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRRC24	ENST00000529415.7	c.1272G>C	p.Met424Ile	missense_variant	Exon 5 of 5	1	NM_001024678.4	ENSP00000434849.1
LRRC14	ENST00000292524.6	c.*1267C>G		3_prime_UTR_variant	Exon 4 of 4	1	NM_014665.4	ENSP00000292524.1
LRRC24	ENST00000533758.1	c.1263G>C	p.Met421Ile	missense_variant	Exon 5 of 5	5		ENSP00000435653.1
LRRC14	ENST00000528528.1	n.164C>G		non_coding_transcript_exon_variant	Exon 1 of 3	3

Frequencies

GnomAD3 genomes AF: 0.000283 AC: 43 AN: 152210 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.000559

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000274 AC: 54 AN: 197274 Hom.: 0 AF XY: 0.000274 AC XY: 30 AN XY: 109652

Gnomad AFR exome AF: 0.000105

Gnomad AMR exome AF: 0.000131

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000553

Gnomad OTH exome AF: 0.000398

GnomAD4 exome AF: 0.000640 AC: 919 AN: 1435330 Hom.: 1 Cov.: 32 AF XY: 0.000617 AC XY: 440 AN XY: 712568

Gnomad4 AFR exome AF: 0.0000629

Gnomad4 AMR exome AF: 0.0000955

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: 0.000806

Gnomad4 OTH exome AF: 0.000439

GnomAD4 genome AF: 0.000282 AC: 43 AN: 152322 Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14 AN XY: 74492

Gnomad4 AFR AF: 0.0000721

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000559

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000425 Hom.: 1

Bravo AF: 0.000340

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000466 AC: 2

ESP6500EA AF: 0.000236 AC: 2

ExAC AF: 0.000161 AC: 19

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 16, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1272G>C (p.M424I) alteration is located in exon 5 (coding exon 4) of the LRRC24 gene. This alteration results from a G to C substitution at nucleotide position 1272, causing the methionine (M) at amino acid position 424 to be replaced by an isoleucine (I). 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	Uncertain	0.35
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.013	T;.
Eigen	Benign	-0.026
Eigen_PC	Benign	0.037
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.83	T;T
M_CAP	Pathogenic	0.48	D
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.049
Sift	Uncertain	0.019	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.67	P;P
Vest4		0.42
MutPred		0.44		Loss of catalytic residue at M424 (P = 0.0602);.;
MVP		0.36
MPC		0.58
ClinPred		0.20	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.41
gMVP		0.34

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: rs200595617; hg19: chr8-145748129;