Genetic Variant HAL:p.Arg322Gln (chr12-95987153-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_002108.4(HAL):c.965G>A(p.Arg322Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000246 in 1,461,198 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R322P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

HAL
NM_002108.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.54

Publications

5 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.86

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002108.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HAL	NM_002108.4	MANE Select	c.965G>A	p.Arg322Gln	missense	Exon 12 of 21	NP_002099.1	P42357-1
HAL	NM_001258334.2		c.965G>A	p.Arg322Gln	missense	Exon 12 of 20	NP_001245263.1	P42357-2
HAL	NM_001258333.2		c.341G>A	p.Arg114Gln	missense	Exon 11 of 20	NP_001245262.1	P42357-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HAL	ENST00000261208.8	TSL:1 MANE Select	c.965G>A	p.Arg322Gln	missense	Exon 12 of 21	ENSP00000261208.3	P42357-1
HAL	ENST00000546999.5	TSL:1	n.*394G>A		non_coding_transcript_exon	Exon 11 of 20	ENSP00000447675.1	Q4VB95
HAL	ENST00000546999.5	TSL:1	n.*394G>A		3_prime_UTR	Exon 11 of 20	ENSP00000447675.1	Q4VB95

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000199

AC:

AN:

251318

AF XY:

0.0000294

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000246

AC:

AN:

1461198

Hom.:

Cov.:

AF XY:

0.0000330

AC XY:

AN XY:

726954

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33460

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.000290

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00000720

AC:

AN:

1111400

Other (OTH)

AF:

0.0000331

AC:

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

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.:

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.59

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.86

MetaSVM

Uncertain

0.25

MutationAssessor

Uncertain

2.3

PhyloP100

7.5

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-3.9

REVEL

Pathogenic

0.78

Sift

Benign

0.047

Sift4G

Benign

0.076

Polyphen

1.0

Vest4

0.89

MutPred

0.69

Loss of methylation at R322 (P = 0.044)

MVP

0.82

MPC

0.66

ClinPred

0.96

GERP RS

5.6

Varity_R

0.55

gMVP

0.78

Mutation Taster

=65/35

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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