NM_001004432.4:c.1330A>T

Variant names:

• chr1-151801375-T-A
• rs61746299
• NM_001004432.4:c.1330A>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001004432.4(LINGO4):​c.1330A>T​(p.Thr444Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0371 in 1,613,770 control chromosomes in the GnomAD database, including 7,318 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.058 (821 hom., cov: 33)
  • Exomes 𝑓: 0.035 (6497 hom.)
• Consequence: LINGO4 NM_001004432.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.207
• Publications: 11 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0012541711).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.35 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001004432.4. 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
	LINGO4	NM_001004432.4	MANE Select	c.1330A>T	p.Thr444Ser	missense	Exon 2 of 2	NP_001004432.1	Q6UY18

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LINGO4	ENST00000368820.4	TSL:1 MANE Select	c.1330A>T	p.Thr444Ser	missense	Exon 2 of 2	ENSP00000357810.4	Q6UY18

Frequencies

GnomAD3 genomes AF: 0.0580 AC: 8824 AN: 152078 Hom.: 823 Cov.: 33

Gnomad AFR AF: 0.0885

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.116

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.364

Gnomad SAS AF: 0.242

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.0478

Gnomad NFE AF: 0.00281

Gnomad OTH AF: 0.0574

GnomAD2 exomes AF: 0.0988 AC: 24825 AN: 251290 AF XY: 0.0954

Gnomad AFR exome AF: 0.0893

Gnomad AMR exome AF: 0.246

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.391

Gnomad FIN exome AF: 0.000463

Gnomad NFE exome AF: 0.00272

Gnomad OTH exome AF: 0.0576

GnomAD4 exome AF: 0.0349 AC: 51010 AN: 1461574 Hom.: 6497 Cov.: 31 AF XY: 0.0389 AC XY: 28302 AN XY: 727038

African (AFR) AF: 0.0919 AC: 3077 AN: 33470

American (AMR) AF: 0.233 AC: 10402 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00191 AC: 50 AN: 26136

East Asian (EAS) AF: 0.334 AC: 13245 AN: 39680

South Asian (SAS) AF: 0.222 AC: 19112 AN: 86248

European-Finnish (FIN) AF: 0.000375 AC: 20 AN: 53384

Middle Eastern (MID) AF: 0.0286 AC: 165 AN: 5768

European-Non Finnish (NFE) AF: 0.00197 AC: 2193 AN: 1111804

Other (OTH) AF: 0.0455 AC: 2746 AN: 60368

GnomAD4 genome AF: 0.0580 AC: 8820 AN: 152196 Hom.: 821 Cov.: 33 AF XY: 0.0639 AC XY: 4756 AN XY: 74430

African (AFR) AF: 0.0886 AC: 3679 AN: 41546

American (AMR) AF: 0.116 AC: 1767 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3470

East Asian (EAS) AF: 0.364 AC: 1875 AN: 5156

South Asian (SAS) AF: 0.241 AC: 1163 AN: 4826

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10612

Middle Eastern (MID) AF: 0.0479 AC: 14 AN: 292

European-Non Finnish (NFE) AF: 0.00281 AC: 191 AN: 67982

Other (OTH) AF: 0.0563 AC: 119 AN: 2114

Alfa AF: 0.0192 Hom.: 238

Bravo AF: 0.0705

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.0849 AC: 374

ESP6500EA AF: 0.00256 AC: 22

ExAC AF: 0.0947 AC: 11494

Asia WGS AF: 0.227 AC: 790 AN: 3478

EpiCase AF: 0.00262

EpiControl AF: 0.00314

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	16
DANN	Benign	0.84
DEOGEN2	Benign	0.089	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.46	T
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.68	N
PhyloP100		0.21
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.020	N
REVEL	Benign	0.10
Sift	Benign	0.71	T
Sift4G	Benign	0.46	T
Polyphen		0.083	B
Vest4		0.042
MutPred		0.42		Gain of disorder (P = 0.0319)
MPC		0.13
ClinPred		0.010	T
GERP RS		5.5
Varity_R		0.049
gMVP		0.18
Mutation Taster		=96/4	polymorphism (auto)

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: rs61746299; hg19: chr1-151773851; COSMIC: COSV63214154; COSMIC: COSV63214154;