Genetic Variant LAX1:p.Pro161His (chr1-203773966-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The NM_017773.4(LAX1):c.482C>A(p.Pro161His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 151,932 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 29)

Consequence

LAX1
NM_017773.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.44

Variant links:

Genes affected

LAX1 (HGNC:26005): (lymphocyte transmembrane adaptor 1) Enables SH2 domain binding activity and protein kinase binding activity. Involved in several processes, including B cell activation; negative regulation of MAP kinase activity; and negative regulation of T cell activation. Located in Golgi apparatus; cytosol; and plasma membrane. Is integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

LAX1 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=0.19199923).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAX1	NM_017773.4 link	c.482C>A	p.Pro161His	missense_variant	Exon 5 of 5	ENST00000442561.7	NP_060243.2	Q8IWV1-1
LAX1	NM_001136190.2 link	c.434C>A	p.Pro145His	missense_variant	Exon 5 of 5		NP_001129662.1	Q8IWV1-3
LAX1	NM_001282878.1 link	c.254C>A	p.Pro85His	missense_variant	Exon 5 of 5		NP_001269807.1	Q8IWV1-2
LAX1	XM_006711397.4 link	c.482C>A	p.Pro161His	missense_variant	Exon 6 of 6		XP_006711460.1	Q8IWV1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LAX1	ENST00000442561.7 link	c.482C>A	p.Pro161His	missense_variant	Exon 5 of 5	1	NM_017773.4	ENSP00000406970.2	Q8IWV1-1
LAX1	ENST00000367215.1 link	n.452C>A		non_coding_transcript_exon_variant	Exon 5 of 5	1
LAX1	ENST00000367217.5 link	c.434C>A	p.Pro145His	missense_variant	Exon 5 of 5	2		ENSP00000356186.5	Q8IWV1-3

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151932

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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

Cov.:

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151932

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74202

show subpopulations

Gnomad4 AFR

AF:

0.0000242

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:

0.0000113

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.482C>A (p.P161H) alteration is located in exon 5 (coding exon 5) of the LAX1 gene. This alteration results from a C to A substitution at nucleotide position 482, causing the proline (P) at amino acid position 161 to be replaced by a histidine (H). 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

0.21

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.59

D;.

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.52

T;T

M_CAP

Benign

0.0047

MetaRNN

Benign

0.19

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

L;.

PrimateAI

Benign

0.25

PROVEAN

Pathogenic

-6.8

D;D

REVEL

Benign

0.23

Sift

Uncertain

0.0050

D;D

Sift4G

Uncertain

0.023

D;D

Polyphen

0.32

B;.

Vest4

0.19

MVP

0.42

MPC

0.55

ClinPred

0.35

GERP RS

3.5

Varity_R

0.28

gMVP

0.032

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