1-151801443-C-G

Variant names:

• chr1-151801443-C-G
• rs143154971
• NM_001004432.4:c.1262G>C

Variant summary

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

The NM_001004432.4(LINGO4):​c.1262G>C​(p.Arg421Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. R421Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: LINGO4 NM_001004432.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.02
• Publications: 3 publications found

Genes affected

LINGO4 (HGNC:31814): (leucine rich repeat and Ig domain containing 4) 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]

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=0.34139386).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LINGO4	NM_001004432.4	c.1262G>C	p.Arg421Pro	missense_variant	Exon 2 of 2	ENST00000368820.4	NP_001004432.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LINGO4	ENST00000368820.4	c.1262G>C	p.Arg421Pro	missense_variant	Exon 2 of 2	1	NM_001004432.4	ENSP00000357810.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251058 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000217

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461784 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727190

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53310

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	1.3	L
PhyloP100		4.0
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.25
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.023	D
Polyphen		0.99	D
Vest4		0.34
MutPred		0.62		Gain of catalytic residue at W422 (P = 0.0116);
MVP		0.82
MPC		0.60
ClinPred		0.80	D
GERP RS		5.5
Varity_R		0.44
gMVP		0.53
Mutation Taster		=65/35	polymorphism

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

Other links and lift over

dbSNP: rs143154971; hg19: chr1-151773919;