chr12-95973615-C-T

Variant names:

• chr12-95973615-C-T
• rs113875416
• NM_002108.4:c.*617G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002108.4(HAL):​c.*617G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.029 in 153,054 control chromosomes in the GnomAD database, including 103 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (102 hom., cov: 32)
  • Exomes 𝑓: 0.027 (1 hom.)
• Consequence: HAL NM_002108.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.159
• Publications: 3 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: Orphanet, ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 12-95973615-C-T is Benign according to our data. Variant chr12-95973615-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 310689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.029 (4421/152242) while in subpopulation NFE AF = 0.0433 (2946/68004). AF 95% confidence interval is 0.042. There are 102 homozygotes in GnomAd4. There are 2213 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 102 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.*617G>A		3_prime_UTR	Exon 21 of 21	NP_002099.1	P42357-1
	HAL	NM_001258334.2		c.*745G>A		3_prime_UTR	Exon 20 of 20	NP_001245263.1	P42357-2
	HAL	NM_001258333.2		c.*617G>A		3_prime_UTR	Exon 20 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.*617G>A		3_prime_UTR	Exon 21 of 21	ENSP00000261208.3	P42357-1
	HAL	ENST00000865988.1		c.*617G>A		3_prime_UTR	Exon 21 of 21	ENSP00000536047.1
	HAL	ENST00000865986.1		c.*617G>A		3_prime_UTR	Exon 21 of 21	ENSP00000536045.1

Frequencies

GnomAD3 genomes AF: 0.0291 AC: 4428 AN: 152124 Hom.: 103 Cov.: 32

Gnomad AFR AF: 0.00664

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.0177

Gnomad ASJ AF: 0.00979

Gnomad EAS AF: 0.0148

Gnomad SAS AF: 0.0350

Gnomad FIN AF: 0.0548

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0434

Gnomad OTH AF: 0.0215

GnomAD4 exome AF: 0.0271 AC: 22 AN: 812 Hom.: 1 Cov.: 0 AF XY: 0.0224 AC XY: 10 AN XY: 446

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AF: 0.00806 AC: 1 AN: 124

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 8

South Asian (SAS) AF: 0.0517 AC: 3 AN: 58

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0304 AC: 18 AN: 592

Other (OTH) AF: 0.00 AC: 0 AN: 22

GnomAD4 genome AF: 0.0290 AC: 4421 AN: 152242 Hom.: 102 Cov.: 32 AF XY: 0.0297 AC XY: 2213 AN XY: 74442

African (AFR) AF: 0.00662 AC: 275 AN: 41532

American (AMR) AF: 0.0176 AC: 270 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00979 AC: 34 AN: 3472

East Asian (EAS) AF: 0.0146 AC: 76 AN: 5188

South Asian (SAS) AF: 0.0346 AC: 167 AN: 4824

European-Finnish (FIN) AF: 0.0548 AC: 581 AN: 10604

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0433 AC: 2946 AN: 68004

Other (OTH) AF: 0.0213 AC: 45 AN: 2112

Alfa AF: 0.0370 Hom.: 171

Bravo AF: 0.0239

Asia WGS AF: 0.0320 AC: 111 AN: 3468

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	-0.90
CADD	Benign	0.55
DANN	Benign	0.27
PhyloP100		-0.16
Mutation Taster		=100/0	polymorphism

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: rs113875416; hg19: chr12-96367393;