Genetic Variant NM_002108.4:c.964C>T (chr12-95987154-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_002108.4(HAL):c.964C>T(p.Arg322*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000533 in 1,613,344 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as association (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0027 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00031 ( 5 hom. )

Consequence

HAL
NM_002108.4 stop_gained

Scores

Clinical Significance

association criteria provided, single submitter O:1

Conservation

PhyloP100: 2.19

Publications

9 publications found

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 Gene-Disease associations (from GenCC):

histidinemia
Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: ClinGen, Orphanet

HAL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HAL	NM_002108.4 link	c.964C>T	p.Arg322*	stop_gained	Exon 12 of 21	ENST00000261208.8	NP_002099.1	P42357-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HAL	ENST00000261208.8 link	c.964C>T	p.Arg322*	stop_gained	Exon 12 of 21	1	NM_002108.4	ENSP00000261208.3		P42357-1

Frequencies

GnomAD3 genomes

AF:

0.00271

AC:

412

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00929

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.000653

AC:

164

AN:

251292

AF XY:

0.000493

show subpopulations

Gnomad AFR exome

AF:

0.00855

Gnomad AMR exome

AF:

0.000376

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000792

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000307

AC:

448

AN:

1461004

Hom.:

Cov.:

AF XY:

0.000270

AC XY:

196

AN XY:

726868

show subpopulations

African (AFR)

AF:

0.00938

AC:

314

AN:

33460

American (AMR)

AF:

0.000335

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.000907

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000450

AC:

AN:

1111206

Other (OTH)

AF:

0.000497

AC:

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

120

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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

AF:

0.00270

AC:

412

AN:

152340

Hom.:

Cov.:

AF XY:

0.00246

AC XY:

183

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.00926

AC:

385

AN:

41574

American (AMR)

AF:

0.000653

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

68032

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

109

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000952

Hom.:

Bravo

AF:

0.00314

ESP6500AA

AF:

0.0104

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000857

AC:

104

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

Significance: association

Submissions summary: Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Increased histidine

Other:1

Nov 15, 2015

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance:association

Review Status:criteria provided, single submitter

Collection Method:research

Three heterozygous loss-of-function variants in HAL were found in 24/1152 African American individuals, in association with elevated serum histidine levels. Histidine level is a potential predictor of cardiovascular risk. Thus, loss-of-function variants in HAL may modify cardiovascular risk. Findings were replicated in a European American cohort. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.62

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.84

PhyloP100

2.2

Vest4

0.97

GERP RS

3.2

Mutation Taster

=2/198

disease causing (fs/PTC)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over