chr12-95972920-G-A

Position:

• chr12-95972920-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002108.4(HAL):​c.*1312C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.352 in 152,134 control chromosomes in the GnomAD database, including 10,668 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (10668 hom., cov: 32)
  • Exomes 𝑓: 0.33 (0 hom.)
• Consequence: HAL NM_002108.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.382

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 12-95972920-G-A is Benign according to our data. Variant chr12-95972920-G-A is described in ClinVar as [Benign]. Clinvar id is 310677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.492 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HAL	NM_002108.4	c.*1312C>T		3_prime_UTR_variant	21/21	ENST00000261208.8	NP_002099.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HAL	ENST00000261208.8	c.*1312C>T		3_prime_UTR_variant	21/21	1	NM_002108.4	ENSP00000261208	P1
HAL	ENST00000541929.5	c.*1312C>T		3_prime_UTR_variant	20/20	2		ENSP00000446364

Frequencies

GnomAD3 genomes AF: 0.352 AC: 53515 AN: 152004 Hom.: 10660 Cov.: 32

Gnomad AFR AF: 0.167

Gnomad AMI AF: 0.339

Gnomad AMR AF: 0.500

Gnomad ASJ AF: 0.484

Gnomad EAS AF: 0.454

Gnomad SAS AF: 0.331

Gnomad FIN AF: 0.376

Gnomad MID AF: 0.366

Gnomad NFE AF: 0.414

Gnomad OTH AF: 0.386

GnomAD4 exome AF: 0.333 AC: 4 AN: 12 Hom.: 0 Cov.: 0 AF XY: 0.333 AC XY: 4 AN XY: 12

Gnomad4 NFE exome AF: 0.375

Gnomad4 OTH exome AF: 0.250

GnomAD4 genome AF: 0.352 AC: 53552 AN: 152122 Hom.: 10668 Cov.: 32 AF XY: 0.356 AC XY: 26458 AN XY: 74346

Gnomad4 AFR AF: 0.167

Gnomad4 AMR AF: 0.501

Gnomad4 ASJ AF: 0.484

Gnomad4 EAS AF: 0.454

Gnomad4 SAS AF: 0.329

Gnomad4 FIN AF: 0.376

Gnomad4 NFE AF: 0.414

Gnomad4 OTH AF: 0.389

Alfa AF: 0.370 Hom.: 4389

Bravo AF: 0.354

Asia WGS AF: 0.398 AC: 1381 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.0
DANN	Benign	0.58
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs1059845; hg19: chr12-96366698;