16-28985490-CTGTG-CTGTGTGTG

Variant names:

• chr16-28985490-C-CTGTG
• rs1363494222
• NM_001014987.2:c.78_81dupTGTG

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_001014987.2(LAT):​c.78_81dupTGTG​(p.His28CysfsTer17) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,588 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LAT NM_001014987.2 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.24

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]

ENSG00000261067 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.883 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAT	NM_001014987.2	c.78_81dupTGTG	p.His28CysfsTer17	frameshift_variant	Exon 1 of 12	ENST00000395456.7	NP_001014987.1
LAT	NM_001014989.2	c.186_189dupTGTG	p.His64CysfsTer17	frameshift_variant	Exon 2 of 13		NP_001014989.2
LAT	NM_014387.4	c.78_81dupTGTG	p.His28CysfsTer17	frameshift_variant	Exon 1 of 11		NP_055202.1
LAT	NM_001014988.2	c.78_81dupTGTG	p.His28CysfsTer17	frameshift_variant	Exon 1 of 12		NP_001014988.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAT	ENST00000395456.7	c.78_81dupTGTG	p.His28CysfsTer17	frameshift_variant	Exon 1 of 12	1	NM_001014987.2	ENSP00000378841.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250850 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135578

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461588 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727106

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1363494222; hg19: chr16-28996811;