chr12-95996374-T-C

Variant names:

• chr12-95996374-T-C
• rs7970524
• NM_002108.4:c.-378A>G

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.-378A>G 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
• Publications: 17 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

ENSG00000257878 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

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.-378A>G		upstream_gene	N/A	NP_002099.1
	HAL	NM_001258334.2		c.-378A>G		upstream_gene	N/A	NP_001245263.1
	HAL	NM_001258333.2		c.-935A>G		upstream_gene	N/A	NP_001245262.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HAL	ENST00000261208.8	TSL:1 MANE Select	c.-378A>G		upstream_gene	N/A	ENSP00000261208.3
	HAL	ENST00000546999.5	TSL:1	n.-378A>G		upstream_gene	N/A	ENSP00000447675.1
	HAL	ENST00000538703.5	TSL:2	c.-378A>G		upstream_gene	N/A	ENSP00000440861.1

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

African (AFR) AF: 0.139 AC: 206 AN: 1478

American (AMR) AF: 0.134 AC: 481 AN: 3602

Ashkenazi Jewish (ASJ) AF: 0.152 AC: 121 AN: 794

East Asian (EAS) AF: 0.0160 AC: 49 AN: 3056

South Asian (SAS) AF: 0.103 AC: 648 AN: 6282

European-Finnish (FIN) AF: 0.172 AC: 285 AN: 1656

Middle Eastern (MID) AF: 0.169 AC: 23 AN: 136

European-Non Finnish (NFE) AF: 0.222 AC: 5161 AN: 23272

Other (OTH) AF: 0.192 AC: 399 AN: 2080

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

African (AFR) AF: 0.159 AC: 6585 AN: 41524

American (AMR) AF: 0.167 AC: 2547 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.194 AC: 674 AN: 3466

East Asian (EAS) AF: 0.0187 AC: 97 AN: 5188

South Asian (SAS) AF: 0.116 AC: 560 AN: 4826

European-Finnish (FIN) AF: 0.164 AC: 1740 AN: 10612

Middle Eastern (MID) AF: 0.173 AC: 51 AN: 294

European-Non Finnish (NFE) AF: 0.258 AC: 17507 AN: 67986

Other (OTH) AF: 0.181 AC: 383 AN: 2112

Alfa AF: 0.232 Hom.: 9177

Bravo AF: 0.198

Asia WGS AF: 0.0690 AC: 241 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Histidinemia (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.2
DANN	Benign	0.41
PhyloP100		0.14
PromoterAI		0.044	Neutral

Splicing

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

Other links and lift over

dbSNP: rs7970524; hg19: chr12-96390152;