12-95980836-C-T

Variant names:

• chr12-95980836-C-T
• rs7297245
• NM_002108.4:c.1315G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002108.4(HAL):​c.1315G>A​(p.Val439Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.806 in 1,578,340 control chromosomes in the GnomAD database, including 516,672 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.86 (56270 hom., cov: 32)
  • Exomes 𝑓: 0.80 (460402 hom.)
• Consequence: HAL NM_002108.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.14
• Publications: 42 publications found

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]

HAL Gene-Disease associations (from GenCC):

• histidinemia

  Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: ClinGen, Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.3329052E-6).
• BP6: Variant 12-95980836-C-T is Benign according to our data. Variant chr12-95980836-C-T is described in ClinVar as Benign. ClinVar VariationId is 310710.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.95 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002108.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HAL	NM_002108.4	MANE Select	c.1315G>A	p.Val439Ile	missense	Exon 16 of 21	NP_002099.1
	HAL	NM_001258334.2		c.1315G>A	p.Val439Ile	missense	Exon 16 of 20	NP_001245263.1
	HAL	NM_001258333.2		c.691G>A	p.Val231Ile	missense	Exon 15 of 20	NP_001245262.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HAL	ENST00000261208.8	TSL:1 MANE Select	c.1315G>A	p.Val439Ile	missense	Exon 16 of 21	ENSP00000261208.3
	HAL	ENST00000546999.5	TSL:1	n.*744G>A		non_coding_transcript_exon	Exon 15 of 20	ENSP00000447675.1
	HAL	ENST00000546999.5	TSL:1	n.*744G>A		3_prime_UTR	Exon 15 of 20	ENSP00000447675.1

Frequencies

GnomAD3 genomes AF: 0.856 AC: 130219 AN: 152086 Hom.: 56211 Cov.: 32

Gnomad AFR AF: 0.958

Gnomad AMI AF: 0.773

Gnomad AMR AF: 0.882

Gnomad ASJ AF: 0.833

Gnomad EAS AF: 0.947

Gnomad SAS AF: 0.891

Gnomad FIN AF: 0.860

Gnomad MID AF: 0.858

Gnomad NFE AF: 0.781

Gnomad OTH AF: 0.857

GnomAD2 exomes AF: 0.847 AC: 212888 AN: 251388 AF XY: 0.844

Gnomad AFR exome AF: 0.964

Gnomad AMR exome AF: 0.901

Gnomad ASJ exome AF: 0.847

Gnomad EAS exome AF: 0.941

Gnomad FIN exome AF: 0.849

Gnomad NFE exome AF: 0.789

Gnomad OTH exome AF: 0.831

GnomAD4 exome AF: 0.801 AC: 1142487 AN: 1426136 Hom.: 460402 Cov.: 30 AF XY: 0.803 AC XY: 571815 AN XY: 711720

African (AFR) AF: 0.969 AC: 31834 AN: 32838

American (AMR) AF: 0.898 AC: 40118 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.846 AC: 21931 AN: 25938

East Asian (EAS) AF: 0.958 AC: 37837 AN: 39510

South Asian (SAS) AF: 0.882 AC: 75424 AN: 85556

European-Finnish (FIN) AF: 0.843 AC: 45023 AN: 53398

Middle Eastern (MID) AF: 0.869 AC: 4962 AN: 5712

European-Non Finnish (NFE) AF: 0.776 AC: 837136 AN: 1079390

Other (OTH) AF: 0.816 AC: 48222 AN: 59104

GnomAD4 genome AF: 0.856 AC: 130337 AN: 152204 Hom.: 56270 Cov.: 32 AF XY: 0.862 AC XY: 64162 AN XY: 74432

African (AFR) AF: 0.958 AC: 39782 AN: 41520

American (AMR) AF: 0.882 AC: 13498 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.833 AC: 2889 AN: 3468

East Asian (EAS) AF: 0.947 AC: 4902 AN: 5178

South Asian (SAS) AF: 0.891 AC: 4299 AN: 4826

European-Finnish (FIN) AF: 0.860 AC: 9117 AN: 10596

Middle Eastern (MID) AF: 0.857 AC: 252 AN: 294

European-Non Finnish (NFE) AF: 0.781 AC: 53081 AN: 68000

Other (OTH) AF: 0.859 AC: 1812 AN: 2110

Alfa AF: 0.814 Hom.: 147120

Bravo AF: 0.863

TwinsUK AF: 0.761 AC: 2822

ALSPAC AF: 0.771 AC: 2970

ESP6500AA AF: 0.955 AC: 4208

ESP6500EA AF: 0.785 AC: 6754

ExAC AF: 0.847 AC: 102812

Asia WGS AF: 0.925 AC: 3216 AN: 3478

EpiCase AF: 0.793

EpiControl AF: 0.787

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Histidinemia Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

HAL-related disorder Benign:1

Oct 16, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	7.0
DANN	Benign	0.082
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0000013	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-1.1	N
PhyloP100		2.1
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	0.48	N
REVEL	Benign	0.20
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.028
MPC		0.11
ClinPred		0.0018	T
GERP RS		4.8
PromoterAI		-0.0052	Neutral
Varity_R		0.057
gMVP		0.34
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs7297245; hg19: chr12-96374614; COSMIC: COSV107196146; COSMIC: COSV107196146;