1-203765641-C-G

Variant names:

• chr1-203765641-C-G
• rs555819774
• NM_017773.4:c.76C>G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_017773.4(LAX1):​c.76C>G​(p.Arg26Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LAX1 NM_017773.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.796

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.028311074).
• BP6: Variant 1-203765641-C-G is Benign according to our data. Variant chr1-203765641-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 2302449.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAX1	NM_017773.4	c.76C>G	p.Arg26Gly	missense_variant	Exon 1 of 5	ENST00000442561.7	NP_060243.2
LAX1	XM_006711397.4	c.76C>G	p.Arg26Gly	missense_variant	Exon 2 of 6		XP_006711460.1
LAX1	NM_001136190.2	c.41+258C>G		intron_variant	Intron 1 of 4		NP_001129662.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAX1	ENST00000442561.7	c.76C>G	p.Arg26Gly	missense_variant	Exon 1 of 5	1	NM_017773.4	ENSP00000406970.2
LAX1	ENST00000367217.5	c.41+258C>G		intron_variant	Intron 1 of 4	2		ENSP00000356186.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461790 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727184

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jul 19, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.091
DANN	Benign	0.79
DEOGEN2	Benign	0.073	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0048	N
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.0017	T
MetaRNN	Benign	0.028	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.5	N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	3.0	N
REVEL	Benign	0.022
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.057
MutPred		0.22		Gain of glycosylation at S27 (P = 0.0831);
MVP		0.29
MPC		0.13
ClinPred		0.060	T
GERP RS		-3.3
Varity_R		0.059
gMVP		0.059

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

Other links and lift over

dbSNP: rs555819774; hg19: chr1-203734769;