chr12-95983909-A-G

Variant names:

• chr12-95983909-A-G
• rs141634423
• NM_002108.4:c.1287+2T>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_002108.4(HAL):​c.1287+2T>C variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000244 in 1,467,544 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance,association (★★).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: HAL NM_002108.4 splice_donor, intron
• Scores: Splicing: ADA: 0.9732
• Clinical Significance: Uncertain significance; association criteria provided, multiple submitters, no conflicts U:1 O:1
• Conservation: PhyloP100: 8.85

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 Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.041033436 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6, offset of 46, new splice context is: ctgGTaatt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HAL	NM_002108.4	c.1287+2T>C		splice_donor_variant, intron_variant	Intron 15 of 20	ENST00000261208.8	NP_002099.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HAL	ENST00000261208.8	c.1287+2T>C		splice_donor_variant, intron_variant	Intron 15 of 20	1	NM_002108.4	ENSP00000261208.3

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152238 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000200 AC: 50 AN: 250290 Hom.: 0 AF XY: 0.000185 AC XY: 25 AN XY: 135270

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000985

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000397

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000255 AC: 335 AN: 1315306 Hom.: 0 Cov.: 22 AF XY: 0.000242 AC XY: 160 AN XY: 662202

Gnomad4 AFR exome AF: 0.0000326

Gnomad4 AMR exome AF: 0.0000449

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000481

Gnomad4 FIN exome AF: 0.0000751

Gnomad4 NFE exome AF: 0.000325

Gnomad4 OTH exome AF: 0.000108

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152238 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74376

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000299 Hom.: 0

Bravo AF: 0.000227

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000214 AC: 26

EpiCase AF: 0.00

EpiControl AF: 0.000237

ClinVar

Significance: Uncertain significance; association

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Histidinemia Uncertain:1

Oct 19, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HAL c.1287+2T>C variant occurs in a canonical splice site (donor) site and is therefore predicted to disrupt or distort the normal gene product. This variant has been reported in one study in which it is found in a heterozygous state in one individual with raised histidine levels from the Atherosclerosis Risk in Communities (ARIC) study (Yu et al. 2015). Control data are unavailable for the c.1287+2T>C variant, which has been reported at a frequency of 0.00070 in the European American population of the Exome Sequencing Project. The evidence for this variant is limited but in combination with the the potential impact of splice donor variants, the c.1287+2T>C variant is classified as a variant of unknown significance but suspicious for pathogenicity for histidinemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Increased histidine Other:1

Nov 15, 2015

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance: association

Review Status: criteria provided, single submitter

Collection Method: research

Three heterozygous loss-of-function variants in HAL were found in 24/1152 African American individuals, in association with elevated serum histidine levels. Histidine level is a potential predictor of cardiovascular risk. Thus, loss-of-function variants in HAL may modify cardiovascular risk. Findings were replicated in a European American cohort. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.060	T
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
GERP RS		5.3

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
SpliceAI score (max)		0.96		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.70		Position offset: -44
DS_DL_spliceai		0.96		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs141634423; hg19: chr12-96377687;