12-95972733-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002108.4(HAL):c.*1499A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0708 in 152,250 control chromosomes in the GnomAD database, including 694 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.071 (694 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HAL NM_002108.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.36

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 12-95972733-T-C is Benign according to our data. Variant chr12-95972733-T-C is described in ClinVar as [Benign]. Clinvar id is 310673.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.34 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HAL	NM_002108.4	c.*1499A>G		3_prime_UTR_variant	21/21	ENST00000261208.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HAL	ENST00000261208.8	c.*1499A>G		3_prime_UTR_variant	21/21	1	NM_002108.4	P1
HAL	ENST00000541929.5	c.*1499A>G		3_prime_UTR_variant	20/20	2

Frequencies

GnomAD3 genomes AF: 0.0707 AC: 10759 AN: 152132 Hom.: 691 Cov.: 32

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0516

Gnomad ASJ AF: 0.0456

Gnomad EAS AF: 0.353

Gnomad SAS AF: 0.124

Gnomad FIN AF: 0.0467

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0342

Gnomad OTH AF: 0.0718

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 6 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 6

Gnomad4 NFE exome AF: 0.00

GnomAD4 genome AF: 0.0708 AC: 10772 AN: 152250 Hom.: 694 Cov.: 32 AF XY: 0.0730 AC XY: 5432 AN XY: 74456

Gnomad4 AFR AF: 0.106

Gnomad4 AMR AF: 0.0516

Gnomad4 ASJ AF: 0.0456

Gnomad4 EAS AF: 0.354

Gnomad4 SAS AF: 0.123

Gnomad4 FIN AF: 0.0467

Gnomad4 NFE AF: 0.0342

Gnomad4 OTH AF: 0.0772

Alfa AF: 0.0599 Hom.: 59

Bravo AF: 0.0728

Asia WGS AF: 0.237 AC: 825 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Histidinemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	0.95
Dann	Benign	0.53

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: rs3812807; hg19: chr12-96366511;