Genetic Variant NM_001014987.2:c.27C>G (chr16-28985444-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001014987.2(LAT):c.27C>G(p.Cys9Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,484 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. C9C) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

LAT
NM_001014987.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.94

Publications

0 publications found

Variant links:

Genes affected

LAT (HGNC:18874): (linker for activation of T cells) The protein encoded by this gene is phosphorylated by ZAP-70/Syk protein tyrosine kinases following activation of the T-cell antigen receptor (TCR) signal transduction pathway. This transmembrane protein localizes to lipid rafts and acts as a docking site for SH2 domain-containing proteins. Upon phosphorylation, this protein recruits multiple adaptor proteins and downstream signaling molecules into multimolecular signaling complexes located near the site of TCR engagement. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

LAT Gene-Disease associations (from GenCC):

severe combined immunodeficiency due to LAT deficiency
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen

LAT links:

ENSG00000261067 (HGNC:):

ENSG00000261067 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08070785).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001014987.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LAT	NM_001014987.2	MANE Select	c.27C>G	p.Cys9Trp	missense	Exon 1 of 12	NP_001014987.1	O43561-2
LAT	NM_001014989.2		c.135C>G	p.Cys45Trp	missense	Exon 2 of 13	NP_001014989.2	O43561-3
LAT	NM_014387.4		c.27C>G	p.Cys9Trp	missense	Exon 1 of 11	NP_055202.1	O43561-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LAT	ENST00000395456.7	TSL:1 MANE Select	c.27C>G	p.Cys9Trp	missense	Exon 1 of 12	ENSP00000378841.3	O43561-2
LAT	ENST00000395461.7	TSL:1	c.135C>G	p.Cys45Trp	missense	Exon 2 of 13	ENSP00000378845.3	O43561-3
LAT	ENST00000566177.5	TSL:1	c.27C>G	p.Cys9Trp	missense	Exon 1 of 10	ENSP00000456761.1	O43561-5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461484

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727066

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53194

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5714

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111930

Other (OTH)

AF:

0.00

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.46

CADD

Benign

4.6

(source)

DANN

Benign

0.91

DEOGEN2

Uncertain

0.67

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.015

LIST_S2

Benign

0.69

M_CAP

Benign

0.022

MetaRNN

Benign

0.081

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

-2.9

PrimateAI

Benign

0.36

PROVEAN

Uncertain

-2.9

REVEL

Benign

0.062

Sift

Uncertain

0.0020

Sift4G

Benign

0.19

Polyphen

0.73

Vest4

0.26

MutPred

0.36

Loss of sheet (P = 0.0315)

MVP

0.34

MPC

1.3

ClinPred

0.21

GERP RS

-8.0

PromoterAI

0.0018

Neutral

(source)

Varity_R

0.30

gMVP

0.34

Mutation Taster

=97/3

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over