chr12-95980836-C-T

Position:

chr12-95980836-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002108.4(HAL):c.1315G>A(p.Val439Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.806 in 1,578,340 control chromosomes in the GnomAD database, including 516,672 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 (★★).

Frequency

Genomes: 𝑓 0.86 ( 56270 hom., cov: 32)

Exomes 𝑓: 0.80 ( 460402 hom. )

Consequence

HAL
NM_002108.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.14

Variant links:

Genes affected

HAL (HGNC:4806): (histidine ammonia-lyase) Histidine ammonia-lyase is a cytosolic enzyme catalyzing the first reaction in histidine catabolism, the nonoxidative deamination of L-histidine to trans-urocanic acid. Histidine ammonia-lyase defects cause histidinemia which is characterized by increased histidine and histamine and decreased urocanic acid in body fluids. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

HAL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.3329052E-6).

BP6

Variant 12-95980836-C-T is Benign according to our data. Variant chr12-95980836-C-T is described in ClinVar as [Benign]. Clinvar id is 310710.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.95 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HAL	NM_002108.4 linkuse as main transcript	c.1315G>A	p.Val439Ile	missense_variant	16/21	ENST00000261208.8	NP_002099.1	P42357-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HAL	ENST00000261208.8 linkuse as main transcript	c.1315G>A	p.Val439Ile	missense_variant	16/21	1	NM_002108.4	ENSP00000261208.3		P42357-1

Frequencies

GnomAD3 genomes

AF:

0.856

AC:

130219

AN:

152086

Hom.:

56211

Cov.:

show subpopulations

Gnomad AFR

AF:

0.958

Gnomad AMI

AF:

0.773

Gnomad AMR

AF:

0.882

Gnomad ASJ

AF:

0.833

Gnomad EAS

AF:

0.947

Gnomad SAS

AF:

0.891

Gnomad FIN

AF:

0.860

Gnomad MID

AF:

0.858

Gnomad NFE

AF:

0.781

Gnomad OTH

AF:

0.857

GnomAD3 exomes

AF:

0.847

AC:

212888

AN:

251388

Hom.:

90682

AF XY:

0.844

AC XY:

114650

AN XY:

135864

show subpopulations

Gnomad AFR exome

AF:

0.964

Gnomad AMR exome

AF:

0.901

Gnomad ASJ exome

AF:

0.847

Gnomad EAS exome

AF:

0.941

Gnomad SAS exome

AF:

0.883

Gnomad FIN exome

AF:

0.849

Gnomad NFE exome

AF:

0.789

Gnomad OTH exome

AF:

0.831

GnomAD4 exome

AF:

0.801

AC:

1142487

AN:

1426136

Hom.:

460402

Cov.:

AF XY:

0.803

AC XY:

571815

AN XY:

711720

show subpopulations

Gnomad4 AFR exome

AF:

0.969

Gnomad4 AMR exome

AF:

0.898

Gnomad4 ASJ exome

AF:

0.846

Gnomad4 EAS exome

AF:

0.958

Gnomad4 SAS exome

AF:

0.882

Gnomad4 FIN exome

AF:

0.843

Gnomad4 NFE exome

AF:

0.776

Gnomad4 OTH exome

AF:

0.816

GnomAD4 genome

AF:

0.856

AC:

130337

AN:

152204

Hom.:

56270

Cov.:

AF XY:

0.862

AC XY:

64162

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.958

Gnomad4 AMR

AF:

0.882

Gnomad4 ASJ

AF:

0.833

Gnomad4 EAS

AF:

0.947

Gnomad4 SAS

AF:

0.891

Gnomad4 FIN

AF:

0.860

Gnomad4 NFE

AF:

0.781

Gnomad4 OTH

AF:

0.859

Alfa

AF:

0.802

Hom.:

100103

Bravo

AF:

0.863

TwinsUK

AF:

0.761

AC:

2822

ALSPAC

AF:

0.771

AC:

2970

ESP6500AA

AF:

0.955

AC:

4208

ESP6500EA

AF:

0.785

AC:

6754

ExAC

AF:

0.847

AC:

102812

Asia WGS

AF:

0.925

AC:

3216

AN:

3478

EpiCase

AF:

0.793

EpiControl

AF:

0.787

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Histidinemia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

HAL-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 16, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.54

CADD

Benign

7.0

DANN

Benign

0.082

DEOGEN2

Benign

0.13

T;.;.

Eigen

Benign

-0.95

Eigen_PC

Benign

-0.68

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.63

T;T;T

MetaRNN

Benign

0.0000013

T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-1.1

N;.;N

PrimateAI

Uncertain

0.68

PROVEAN

Benign

0.48

N;N;N

REVEL

Benign

0.20

Sift

Benign

1.0

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.028

MPC

0.11

ClinPred

0.0018

GERP RS

4.8

Varity_R

0.057

gMVP

0.34

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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