rs121434330

chr12-95987153-C-Gchr12-95987153-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_002108.4(HAL):c.965G>C(p.Arg322Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,200 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Affects (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HAL NM_002108.4 missense
• Clinical Significance: Affects no assertion criteria provided O:1
• Conservation: PhyloP100: 7.54

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.954

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HAL	NM_002108.4	c.965G>C	p.Arg322Pro	missense_variant	12/21	ENST00000261208.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HAL	ENST00000261208.8	c.965G>C	p.Arg322Pro	missense_variant	12/21	1	NM_002108.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461200 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726956

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Affects

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Histidinemia Other:1

Affects, no assertion criteria provided

literature only

OMIM

Apr 01, 2005

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D;.;.;D
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	T;T;T;T
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Pathogenic	3.8	H;.;H;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-6.8	D;D;D;D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.020	D;T;D;D
Sift4G	Uncertain	0.032	D;T;T;D
Polyphen		1.0	D;.;.;.
Vest4		0.97
MutPred		0.82		Gain of glycosylation at S324 (P = 0.0387);.;Gain of glycosylation at S324 (P = 0.0387);.;
MVP		0.93
MPC		0.75
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.99
gMVP		0.95

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

LitVar

Other links and lift over

dbSNP: rs121434330; hg19: chr12-96380931;