rs141634423

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PVS1_Moderate

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 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: association criteria provided, single submitter O:1
• Conservation: PhyloP100: 8.85
• Publications: 5 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: Uncertain_significance. The variant received 2 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HAL	NM_002108.4	MANE Select	c.1287+2T>C		splice_donor intron	N/A	NP_002099.1	P42357-1
	HAL	NM_001258334.2		c.1287+2T>C		splice_donor intron	N/A	NP_001245263.1	P42357-2
	HAL	NM_001258333.2		c.663+2T>C		splice_donor intron	N/A	NP_001245262.1	P42357-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HAL	ENST00000261208.8	TSL:1 MANE Select	c.1287+2T>C		splice_donor intron	N/A	ENSP00000261208.3	P42357-1
	HAL	ENST00000546999.5	TSL:1	n.*716+2T>C		splice_donor intron	N/A	ENSP00000447675.1	Q4VB95
	HAL	ENST00000865988.1		c.1287+2T>C		splice_donor intron	N/A	ENSP00000536047.1

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

GnomAD2 exomes AF: 0.000200 AC: 50 AN: 250290 AF XY: 0.000185

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 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

African (AFR) AF: 0.0000326 AC: 1 AN: 30628

American (AMR) AF: 0.0000449 AC: 2 AN: 44514

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25184

East Asian (EAS) AF: 0.00 AC: 0 AN: 39054

South Asian (SAS) AF: 0.0000481 AC: 4 AN: 83220

European-Finnish (FIN) AF: 0.0000751 AC: 4 AN: 53240

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4358

European-Non Finnish (NFE) AF: 0.000325 AC: 318 AN: 979744

Other (OTH) AF: 0.000108 AC: 6 AN: 55364

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

African (AFR) AF: 0.0000482 AC: 2 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68038

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.000305 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

ClinVar submissions

Significance: association

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	-	Increased histidine (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		8.9
GERP RS		5.3
Mutation Taster		=0/100	disease causing

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

Other links and lift over

dbSNP: rs141634423; hg19: chr12-96377687;