2-77518538-T-A

Variant names:

• chr2-77518538-T-A
• rs941094225
• NM_001134745.3:c.1331A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001134745.3(LRRTM4):​c.1331A>T​(p.Tyr444Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,218 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Y444C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LRRTM4 NM_001134745.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.02
• Publications: 0 publications found

Genes affected

LRRTM4 (HGNC:19411): (leucine rich repeat transmembrane neuronal 4) Predicted to enable heparan sulfate proteoglycan binding activity. Predicted to be involved in regulation of synapse assembly. Predicted to act upstream of or within AMPA glutamate receptor clustering; positive regulation of synapse assembly; and regulation of presynaptic membrane organization. Predicted to be located in postsynaptic membrane. Predicted to be part of AMPA glutamate receptor complex. Predicted to be active in extracellular matrix; extracellular space; and glutamatergic synapse. Predicted to be integral component of postsynaptic density membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001134745.3. 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
	LRRTM4	NM_001134745.3	MANE Select	c.1331A>T	p.Tyr444Phe	missense	Exon 3 of 4	NP_001128217.1	Q86VH4-1
	LRRTM4	NM_001330370.2		c.1334A>T	p.Tyr445Phe	missense	Exon 2 of 3	NP_001317299.1	B8ZZ84
	LRRTM4	NM_001282924.3		c.1331A>T	p.Tyr444Phe	missense	Exon 3 of 4	NP_001269853.1	Q86VH4-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRTM4	ENST00000409884.6	TSL:1 MANE Select	c.1331A>T	p.Tyr444Phe	missense	Exon 3 of 4	ENSP00000387297.1	Q86VH4-1
	LRRTM4	ENST00000409282.1	TSL:1	c.1334A>T	p.Tyr445Phe	missense	Exon 2 of 2	ENSP00000386286.1	Q4KMX1
	LRRTM4	ENST00000409088.3	TSL:1	c.1331A>T	p.Tyr444Phe	missense	Exon 3 of 3	ENSP00000386236.3	Q86VH4-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461218 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 726894

African (AFR) AF: 0.0000299 AC: 1 AN: 33442

American (AMR) AF: 0.00 AC: 0 AN: 44628

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111614

Other (OTH) AF: 0.00 AC: 0 AN: 60352

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.038	T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.078	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Uncertain	-0.039	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		8.0
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.46
Sift	Benign	0.14	T
Sift4G	Benign	0.12	T
Polyphen		1.0	D
Vest4		0.58
MutPred		0.43		Loss of catalytic residue at Y444 (P = 0.0121)
MVP		0.60
MPC		1.4
ClinPred		0.96	D
GERP RS		5.7
Varity_R		0.33
gMVP		0.36
Mutation Taster		=41/59	disease causing

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: rs941094225; hg19: chr2-77745664;