12-96006401-T-A

Position:

• chr12-96006401-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000228740.7(LTA4H):​c.1443A>T​(p.Glu481Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00424 in 1,599,542 control chromosomes in the GnomAD database, including 233 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E481K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.022 (122 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (111 hom.)
• Consequence: LTA4H ENST00000228740.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.602

Genes affected

LTA4H (HGNC:6710): (leukotriene A4 hydrolase) The protein encoded by this gene is an enzyme that contains both hydrolase and aminopeptidase activities. The hydrolase activity is used in the final step of the biosynthesis of leukotriene B4, a proinflammatory mediator. The aminopeptidase activity has been shown to degrade proline-glycine-proline (PGP), a neutrophil chemoattractant and biomarker for chronic obstructive pulmonary disease (COPD). Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2015]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018874407).
• BP6: Variant 12-96006401-T-A is Benign according to our data. Variant chr12-96006401-T-A is described in ClinVar as [Benign]. Clinvar id is 718094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0738 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LTA4H	NM_000895.3	c.1443A>T	p.Glu481Asp	missense_variant	16/19	ENST00000228740.7	NP_000886.1
LOC102723340	XR_945236.4	n.741-3560T>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LTA4H	ENST00000228740.7	c.1443A>T	p.Glu481Asp	missense_variant	16/19	1	NM_000895.3	ENSP00000228740	P1
	ENST00000551849.2	n.342-3560T>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0220 AC: 3353 AN: 152186 Hom.: 120 Cov.: 32

Gnomad AFR AF: 0.0760

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00969

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000413

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.0153

GnomAD3 exomes AF: 0.00586 AC: 1459 AN: 248866 Hom.: 32 AF XY: 0.00415 AC XY: 558 AN XY: 134530

Gnomad AFR exome AF: 0.0777

Gnomad AMR exome AF: 0.00445

Gnomad ASJ exome AF: 0.000599

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000100

Gnomad FIN exome AF: 0.0000470

Gnomad NFE exome AF: 0.000186

Gnomad OTH exome AF: 0.00330

GnomAD4 exome AF: 0.00237 AC: 3424 AN: 1447238 Hom.: 111 Cov.: 26 AF XY: 0.00199 AC XY: 1431 AN XY: 720524

Gnomad4 AFR exome AF: 0.0778

Gnomad4 AMR exome AF: 0.00560

Gnomad4 ASJ exome AF: 0.000848

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000129

Gnomad4 FIN exome AF: 0.0000190

Gnomad4 NFE exome AF: 0.000192

Gnomad4 OTH exome AF: 0.00567

GnomAD4 genome AF: 0.0221 AC: 3364 AN: 152304 Hom.: 122 Cov.: 32 AF XY: 0.0206 AC XY: 1535 AN XY: 74498

Gnomad4 AFR AF: 0.0760

Gnomad4 AMR AF: 0.00967

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.0151

Alfa AF: 0.00645 Hom.: 10

Bravo AF: 0.0255

ESP6500AA AF: 0.0742 AC: 327

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00705 AC: 856

Asia WGS AF: 0.00664 AC: 23 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 31, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.11	T;.;.
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.80	T;T;T
MetaRNN	Benign	0.0019	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.88	L;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.097
Sift	Benign	0.20	T;T;T
Sift4G	Benign	0.40	T;T;T
Polyphen		0.0	B;.;B
Vest4		0.20
MutPred		0.38		Gain of catalytic residue at N485 (P = 0.0428);.;.;
MVP		0.40
MPC		0.24
ClinPred		0.0034	T
GERP RS		-0.28
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.33
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs45630739; hg19: chr12-96400179;