Genetic Variant HAL:p.Arg206Lys (chr12-95992778-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_002108.4(HAL):c.617G>A(p.Arg206Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,460,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. R206T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

HAL
NM_002108.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.77

Publications

4 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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.32722378).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HAL	NM_002108.4 link	c.617G>A	p.Arg206Lys	missense_variant	Exon 9 of 21	ENST00000261208.8	NP_002099.1	P42357-1
HAL	NM_001258334.2 link	c.617G>A	p.Arg206Lys	missense_variant	Exon 9 of 20		NP_001245263.1	P42357-2
HAL	NM_001258333.2 link	c.-8G>A		5_prime_UTR_variant	Exon 8 of 20		NP_001245262.1	P42357-3
HAL	XM_011538249.3 link	c.-96G>A		upstream_gene_variant			XP_011536551.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HAL	ENST00000261208.8 link	c.617G>A	p.Arg206Lys	missense_variant	Exon 9 of 21	1	NM_002108.4	ENSP00000261208.3		P42357-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000318

AC:

AN:

251484

AF XY:

0.0000368

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000231

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:

0.00000479

AC:

AN:

1460528

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

726654

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33450

American (AMR)

AF:

0.000134

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26102

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.00

AC:

AN:

86224

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110844

Other (OTH)

AF:

0.0000166

AC:

AN:

60344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.062

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.30

T;.;T;.

Eigen

Benign

-0.13

Eigen_PC

Benign

0.028

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.79

T;T;T;T

M_CAP

Benign

0.074

MetaRNN

Benign

0.33

T;T;T;T

MetaSVM

Benign

-0.54

MutationAssessor

Benign

1.7

L;L;.;.

PhyloP100

5.8

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-1.8

N;N;N;N

REVEL

Uncertain

0.44

Sift

Benign

0.76

T;T;T;T

Sift4G

Benign

0.77

T;T;T;.

Polyphen

0.020

B;.;.;.

Vest4

0.51

MutPred

0.60

Gain of catalytic residue at L202 (P = 3e-04);Gain of catalytic residue at L202 (P = 3e-04);.;.;

MVP

0.58

MPC

0.16

ClinPred

0.13

GERP RS

4.8

Varity_R

0.39

gMVP

0.86

Mutation Taster

=36/64

disease causing

(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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12-95992778-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over