12-95972991-T-G

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.*1241A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.44 in 152,094 control chromosomes in the GnomAD database, including 14,916 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.44 (14914 hom., cov: 32)
  • Exomes 𝑓: 0.50 (2 hom.)
• Consequence: HAL NM_002108.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.110

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=-0.87).
• BP6: Variant 12-95972991-T-G is Benign according to our data. Variant chr12-95972991-T-G is described in ClinVar as [Benign]. Clinvar id is 310679.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.523 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HAL	NM_002108.4	c.*1241A>C		3_prime_UTR_variant	21/21	ENST00000261208.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HAL	ENST00000261208.8	c.*1241A>C		3_prime_UTR_variant	21/21	1	NM_002108.4	P1
HAL	ENST00000541929.5	c.*1241A>C		3_prime_UTR_variant	20/20	2

Frequencies

GnomAD3 genomes AF: 0.440 AC: 66793 AN: 151966 Hom.: 14886 Cov.: 32

Gnomad AFR AF: 0.471

Gnomad AMI AF: 0.362

Gnomad AMR AF: 0.532

Gnomad ASJ AF: 0.483

Gnomad EAS AF: 0.466

Gnomad SAS AF: 0.322

Gnomad FIN AF: 0.375

Gnomad MID AF: 0.383

Gnomad NFE AF: 0.415

Gnomad OTH AF: 0.442

GnomAD4 exome AF: 0.500 AC: 5 AN: 10 Hom.: 2 Cov.: 0 AF XY: 0.167 AC XY: 1 AN XY: 6

Gnomad4 NFE exome AF: 0.750

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.440 AC: 66869 AN: 152084 Hom.: 14914 Cov.: 32 AF XY: 0.439 AC XY: 32645 AN XY: 74320

Gnomad4 AFR AF: 0.471

Gnomad4 AMR AF: 0.533

Gnomad4 ASJ AF: 0.483

Gnomad4 EAS AF: 0.466

Gnomad4 SAS AF: 0.321

Gnomad4 FIN AF: 0.375

Gnomad4 NFE AF: 0.415

Gnomad4 OTH AF: 0.445

Alfa AF: 0.428 Hom.: 3075

Bravo AF: 0.454

Asia WGS AF: 0.420 AC: 1457 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 12, 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	-0.87
Cadd	Benign	5.7
Dann	Benign	0.62

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: rs1059844; hg19: chr12-96366769;