Variant 2-76748829-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001134745.3(LRRTM4):c.1639A>C(p.Thr547Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,132 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.0000066 ( 0 hom., cov: 32)

Consequence

LRRTM4
NM_001134745.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.82

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:

LRRTM4 (HGNC:):

LRRTM4 links:

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ACMG classification

Classification made for transcript

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=0.080237985).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRRTM4	NM_001134745.3 linkuse as main transcript	c.1639A>C	p.Thr547Pro	missense_variant	4/4	ENST00000409884.6	NP_001128217.1	Q86VH4-1Q6ZT31
LRRTM4	NM_001330370.2 linkuse as main transcript	c.1642A>C	p.Thr548Pro	missense_variant	3/3		NP_001317299.1	B8ZZ84
LRRTM4	NM_001282924.3 linkuse as main transcript	c.1639A>C	p.Thr547Pro	missense_variant	4/4		NP_001269853.1	Q86VH4-1B3KV11
LRRTM4	NR_146416.2 linkuse as main transcript	n.356A>C		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
LRRTM4	ENST00000409884.6 linkuse as main transcript	c.1639A>C	p.Thr547Pro	missense_variant	4/4	1	NM_001134745.3	ENSP00000387297.1	Q86VH4-1
LRRTM4	ENST00000409911.5 linkuse as main transcript	c.1642A>C	p.Thr548Pro	missense_variant	3/3	5		ENSP00000387228.1	B8ZZ84
LRRTM4	ENST00000409093.1 linkuse as main transcript	c.1639A>C	p.Thr547Pro	missense_variant	4/4	2		ENSP00000386357.1	Q86VH4-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152132

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

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

Aug 27, 2024

The c.1639A>C (p.T547P) alteration is located in exon 4 (coding exon 3) of the LRRTM4 gene. This alteration results from a A to C substitution at nucleotide position 1639, causing the threonine (T) at amino acid position 547 to be replaced by a proline (P). 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

0.060

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Benign

0.65

DEOGEN2

Benign

0.0070

T;T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.97

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.56

T;.;T

M_CAP

Benign

0.010

MetaRNN

Benign

0.080

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

.;N;N

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.37

N;N;N

REVEL

Benign

0.093

Sift

Uncertain

0.022

D;D;D

Sift4G

Uncertain

0.040

D;D;D

Polyphen

0.0020

.;B;B

Vest4

0.20

MutPred

0.20

.;Gain of disorder (P = 0.0548);Gain of disorder (P = 0.0548);

MVP

0.068

MPC

0.74

ClinPred

0.069

GERP RS

-0.93

Varity_R

0.089

gMVP

0.62

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