2-76748835-G-A

Variant names:

• chr2-76748835-G-A
• NM_001134745.3:c.1633C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001134745.3(LRRTM4):​c.1633C>T​(p.His545Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,710 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: LRRTM4 NM_001134745.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.14

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1750023).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRTM4	NM_001134745.3	c.1633C>T	p.His545Tyr	missense_variant	Exon 4 of 4	ENST00000409884.6	NP_001128217.1
LRRTM4	NM_001330370.2	c.1636C>T	p.His546Tyr	missense_variant	Exon 3 of 3		NP_001317299.1
LRRTM4	NM_001282924.3	c.1633C>T	p.His545Tyr	missense_variant	Exon 4 of 4		NP_001269853.1
LRRTM4	NR_146416.2	n.350C>T		non_coding_transcript_exon_variant	Exon 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRRTM4	ENST00000409884.6	c.1633C>T	p.His545Tyr	missense_variant	Exon 4 of 4	1	NM_001134745.3	ENSP00000387297.1
LRRTM4	ENST00000409911.5	c.1636C>T	p.His546Tyr	missense_variant	Exon 3 of 3	5		ENSP00000387228.1
LRRTM4	ENST00000409093.1	c.1633C>T	p.His545Tyr	missense_variant	Exon 4 of 4	2		ENSP00000386357.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461710 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 727136

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1633C>T (p.H545Y) alteration is located in exon 4 (coding exon 3) of the LRRTM4 gene. This alteration results from a C to T substitution at nucleotide position 1633, causing the histidine (H) at amino acid position 545 to be replaced by a tyrosine (Y). 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	Benign	0.089
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.012	T;T;T
Eigen	Benign	-0.16
Eigen_PC	Benign	0.013
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.77	T;.;T
M_CAP	Benign	0.0075	T
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	.;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.16	N;N;N
REVEL	Benign	0.067
Sift	Benign	0.096	T;T;T
Sift4G	Benign	0.26	T;T;T
Polyphen		0.079	.;B;B
Vest4		0.37
MutPred		0.25		.;Loss of disorder (P = 0.0603);Loss of disorder (P = 0.0603);
MVP		0.068
MPC		0.68
ClinPred		0.45	T
GERP RS		5.9
Varity_R		0.11
gMVP		0.42

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-76975961;