chr2-76748741-G-A

Position:

• chr2-76748741-G-A

Variant summary

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

The NM_001134745.3(LRRTM4):​c.1727C>T​(p.Ala576Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000103 in 1,461,668 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.25804675).
• BS2: High AC in GnomAdExome4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRTM4	NM_001134745.3	c.1727C>T	p.Ala576Val	missense_variant	4/4	ENST00000409884.6
LRRTM4	NM_001330370.2	c.1730C>T	p.Ala577Val	missense_variant	3/3
LRRTM4	NM_001282924.3	c.1727C>T	p.Ala576Val	missense_variant	4/4
LRRTM4	NR_146416.2	n.444C>T		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRTM4	ENST00000409884.6	c.1727C>T	p.Ala576Val	missense_variant	4/4	1	NM_001134745.3	P4
LRRTM4	ENST00000409911.5	c.1730C>T	p.Ala577Val	missense_variant	3/3	5		A1
LRRTM4	ENST00000409093.1	c.1727C>T	p.Ala576Val	missense_variant	4/4	2		P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461668 Hom.: 0 Cov.: 34 AF XY: 0.00000688 AC XY: 5 AN XY: 727122

Gnomad4 AFR exome AF: 0.00

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: 0.0000135

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2022

The c.1727C>T (p.A576V) 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 1727, causing the alanine (A) at amino acid position 576 to be replaced by a valine (V). 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	0.54
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0092	T;T;T
Eigen	Benign	0.19
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.63	T;.;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.26	T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.81	.;L;L
MutationTaster	Benign	0.64	N;N;N
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	0.10	N;N;N
REVEL	Benign	0.098
Sift	Uncertain	0.0080	D;D;D
Sift4G	Uncertain	0.021	D;D;D
Polyphen		0.30	.;B;B
Vest4		0.48
MutPred		0.31		.;Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);
MVP		0.10
MPC		1.0
ClinPred		0.84	D
GERP RS		5.7
Varity_R		0.16
gMVP		0.57

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: chr2-76975867;