Variant chr2-76748774-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001134745.3(LRRTM4):c.1694T>G(p.Leu565Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

LRRTM4
NM_001134745.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.82

Variant links:

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]

LRRTM4 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.17898849).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
LRRTM4	NM_001134745.3 linkuse as main transcript	c.1694T>G	p.Leu565Arg	missense_variant	4/4	ENST00000409884.6
LRRTM4	NM_001330370.2 linkuse as main transcript	c.1697T>G	p.Leu566Arg	missense_variant	3/3
LRRTM4	NM_001282924.3 linkuse as main transcript	c.1694T>G	p.Leu565Arg	missense_variant	4/4
LRRTM4	NR_146416.2 linkuse as main transcript	n.411T>G		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRTM4	ENST00000409884.6 linkuse as main transcript	c.1694T>G	p.Leu565Arg	missense_variant	4/4	1	NM_001134745.3	P4	Q86VH4-1
LRRTM4	ENST00000409911.5 linkuse as main transcript	c.1697T>G	p.Leu566Arg	missense_variant	3/3	5		A1
LRRTM4	ENST00000409093.1 linkuse as main transcript	c.1694T>G	p.Leu565Arg	missense_variant	4/4	2		P4	Q86VH4-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152064

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461710

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727136

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

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

AF:

0.0000197

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2023

The c.1694T>G (p.L565R) alteration is located in exon 4 (coding exon 3) of the LRRTM4 gene. This alteration results from a T to G substitution at nucleotide position 1694, causing the leucine (L) at amino acid position 565 to be replaced by an arginine (R). 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

0.068

BayesDel_addAF

Uncertain

0.097

BayesDel_noAF

Benign

-0.10

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0091

T;T;T

Eigen

Benign

0.13

Eigen_PC

Benign

0.22

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.50

T;.;T

M_CAP

Benign

0.024

MetaRNN

Benign

0.18

T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.69

.;N;N

MutationTaster

Benign

0.89

D;D;D

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.17

N;N;N

REVEL

Benign

0.18

Sift

Uncertain

0.011

D;T;T

Sift4G

Benign

0.28

T;T;T

Polyphen

0.94

.;P;P

Vest4

0.35

MutPred

0.25

.;Gain of solvent accessibility (P = 1e-04);Gain of solvent accessibility (P = 1e-04);

MVP

0.73

MPC

1.5

ClinPred

0.87

GERP RS

5.9

Varity_R

0.25

gMVP

0.82

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over