rs34457757

Variant names:

• chr12-95987154-G-A
• rs34457757
• NM_002108.4:c.964C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-95987154-G-A
• chr12-95987154-G-C
• chr12-95987154-G-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_002108.4(HAL):​c.964C>T​(p.Arg322*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000533 in 1,613,344 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as association (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (5 hom.)
• Consequence: HAL NM_002108.4 stop_gained
• Clinical Significance: association criteria provided, single submitter O:1
• Conservation: PhyloP100: 2.19
• Publications: 9 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

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.964C>T	p.Arg322*	stop_gained	Exon 12 of 21	NP_002099.1	P42357-1
	HAL	NM_001258334.2		c.964C>T	p.Arg322*	stop_gained	Exon 12 of 20	NP_001245263.1	P42357-2
	HAL	NM_001258333.2		c.340C>T	p.Arg114*	stop_gained	Exon 11 of 20	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.964C>T	p.Arg322*	stop_gained	Exon 12 of 21	ENSP00000261208.3	P42357-1
	HAL	ENST00000546999.5	TSL:1	n.*393C>T		non_coding_transcript_exon	Exon 11 of 20	ENSP00000447675.1	Q4VB95
	HAL	ENST00000546999.5	TSL:1	n.*393C>T		3_prime_UTR	Exon 11 of 20	ENSP00000447675.1	Q4VB95

Frequencies

GnomAD3 genomes AF: 0.00271 AC: 412 AN: 152222 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00929

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000653 AC: 164 AN: 251292 AF XY: 0.000493

Gnomad AFR exome AF: 0.00855

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000792

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000307 AC: 448 AN: 1461004 Hom.: 5 Cov.: 31 AF XY: 0.000270 AC XY: 196 AN XY: 726868

African (AFR) AF: 0.00938 AC: 314 AN: 33460

American (AMR) AF: 0.000335 AC: 15 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.000907 AC: 36 AN: 39694

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.0000450 AC: 50 AN: 1111206

Other (OTH) AF: 0.000497 AC: 30 AN: 60358

GnomAD4 genome AF: 0.00270 AC: 412 AN: 152340 Hom.: 0 Cov.: 32 AF XY: 0.00246 AC XY: 183 AN XY: 74498

African (AFR) AF: 0.00926 AC: 385 AN: 41574

American (AMR) AF: 0.000653 AC: 10 AN: 15304

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

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68032

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.000952 Hom.: 2

Bravo AF: 0.00314

ESP6500AA AF: 0.0104 AC: 46

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000857 AC: 104

EpiCase AF: 0.00

EpiControl AF: 0.000178

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	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.84	D
PhyloP100		2.2
Vest4		0.97
GERP RS		3.2
Mutation Taster		=2/198	disease causing (fs/PTC)

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

Other links and lift over

dbSNP: rs34457757; hg19: chr12-96380932; COSMIC: COSV54120619; COSMIC: COSV54120619;