rs7970524

Positions:

• chr12-95996374-T-C

Variant summary

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

The 12-95996374-T-C variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.194 in 194,572 control chromosomes in the GnomAD database, including 4,175 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3321 hom., cov: 33)
  • Exomes 𝑓: 0.17 (854 hom.)
• Consequence: HAL NM_002108.4 upstream_gene
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.144

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=-0.81).
• BP6: Variant 12-95996374-T-C is Benign according to our data. Variant chr12-95996374-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 369030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.254 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HAL	NM_002108.4			upstream_gene_variant		ENST00000261208.8	NP_002099.1
HAL	NM_001258333.2			upstream_gene_variant			NP_001245262.1
HAL	NM_001258334.2			upstream_gene_variant			NP_001245263.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HAL	ENST00000261208.8			upstream_gene_variant		1	NM_002108.4	ENSP00000261208	P1
HAL	ENST00000538703.5			upstream_gene_variant		2		ENSP00000440861
HAL	ENST00000541929.5			upstream_gene_variant		2		ENSP00000446364

Frequencies

GnomAD3 genomes AF: 0.199 AC: 30334 AN: 152098 Hom.: 3321 Cov.: 33

Gnomad AFR AF: 0.159

Gnomad AMI AF: 0.209

Gnomad AMR AF: 0.167

Gnomad ASJ AF: 0.194

Gnomad EAS AF: 0.0187

Gnomad SAS AF: 0.116

Gnomad FIN AF: 0.164

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.257

Gnomad OTH AF: 0.184

GnomAD4 exome AF: 0.174 AC: 7373 AN: 42356 Hom.: 854 Cov.: 0 AF XY: 0.168 AC XY: 3702 AN XY: 21978

Gnomad4 AFR exome AF: 0.139

Gnomad4 AMR exome AF: 0.134

Gnomad4 ASJ exome AF: 0.152

Gnomad4 EAS exome AF: 0.0160

Gnomad4 SAS exome AF: 0.103

Gnomad4 FIN exome AF: 0.172

Gnomad4 NFE exome AF: 0.222

Gnomad4 OTH exome AF: 0.192

GnomAD4 genome AF: 0.199 AC: 30335 AN: 152216 Hom.: 3321 Cov.: 33 AF XY: 0.192 AC XY: 14259 AN XY: 74440

Gnomad4 AFR AF: 0.159

Gnomad4 AMR AF: 0.167

Gnomad4 ASJ AF: 0.194

Gnomad4 EAS AF: 0.0187

Gnomad4 SAS AF: 0.116

Gnomad4 FIN AF: 0.164

Gnomad4 NFE AF: 0.258

Gnomad4 OTH AF: 0.181

Alfa AF: 0.227 Hom.: 2555

Bravo AF: 0.198

Asia WGS AF: 0.0690 AC: 241 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Histidinemia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Likely 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	-0.81
CADD	Benign	6.2
DANN	Benign	0.41

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs7970524; hg19: chr12-96390152;