12-95973615-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_002108.4(HAL):c.*617G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.029 in 153,054 control chromosomes in the GnomAD database, including 103 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.029 (102 hom., cov: 32)
  • Exomes 𝑓: 0.027 (1 hom.)
• Consequence: HAL NM_002108.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.159

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=-0.9).
• BP6: Variant 12-95973615-C-T is Benign according to our data. Variant chr12-95973615-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 310689.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.029 (4421/152242) while in subpopulation NFE AF= 0.0433 (2946/68004). AF 95% confidence interval is 0.042. There are 102 homozygotes in gnomad4. There are 2213 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 103 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HAL	NM_002108.4	c.*617G>A		3_prime_UTR_variant	21/21	ENST00000261208.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HAL	ENST00000261208.8	c.*617G>A		3_prime_UTR_variant	21/21	1	NM_002108.4	P1
HAL	ENST00000541929.5	c.*617G>A		3_prime_UTR_variant	20/20	2
HAL	ENST00000544080.6			downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.0291 AC: 4428 AN: 152124 Hom.: 103 Cov.: 32

Gnomad AFR AF: 0.00664

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.0177

Gnomad ASJ AF: 0.00979

Gnomad EAS AF: 0.0148

Gnomad SAS AF: 0.0350

Gnomad FIN AF: 0.0548

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0434

Gnomad OTH AF: 0.0215

GnomAD4 exome AF: 0.0271 AC: 22 AN: 812 Hom.: 1 Cov.: 0 AF XY: 0.0224 AC XY: 10 AN XY: 446

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00806

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0517

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0304

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0290 AC: 4421 AN: 152242 Hom.: 102 Cov.: 32 AF XY: 0.0297 AC XY: 2213 AN XY: 74442

Gnomad4 AFR AF: 0.00662

Gnomad4 AMR AF: 0.0176

Gnomad4 ASJ AF: 0.00979

Gnomad4 EAS AF: 0.0146

Gnomad4 SAS AF: 0.0346

Gnomad4 FIN AF: 0.0548

Gnomad4 NFE AF: 0.0433

Gnomad4 OTH AF: 0.0213

Alfa AF: 0.0381 Hom.: 25

Bravo AF: 0.0239

Asia WGS AF: 0.0320 AC: 111 AN: 3468

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Histidinemia Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.55
Dann	Benign	0.27

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: rs113875416; hg19: chr12-96367393;