rs61937878

Variant names:

• chr12-95977953-C-T
• rs61937878
• NM_002108.4:c.1645G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_002108.4(HAL):​c.1645G>A​(p.Val549Met) variant causes a missense change. The variant allele was found at a frequency of 0.00437 in 1,614,124 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0025 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (22 hom.)
• Consequence: HAL NM_002108.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.77
• Publications: 12 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.040305644).
• BS2: High Homozygotes in GnomAdExome4 at 22 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.1645G>A	p.Val549Met	missense	Exon 18 of 21	NP_002099.1	P42357-1
	HAL	NM_001258334.2		c.1645G>A	p.Val549Met	missense	Exon 18 of 20	NP_001245263.1	P42357-2
	HAL	NM_001258333.2		c.1021G>A	p.Val341Met	missense	Exon 17 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.1645G>A	p.Val549Met	missense	Exon 18 of 21	ENSP00000261208.3	P42357-1
	HAL	ENST00000546999.5	TSL:1	n.*1057G>A		non_coding_transcript_exon	Exon 17 of 20	ENSP00000447675.1	Q4VB95
	HAL	ENST00000546999.5	TSL:1	n.*1057G>A		3_prime_UTR	Exon 17 of 20	ENSP00000447675.1	Q4VB95

Frequencies

GnomAD3 genomes AF: 0.00251 AC: 382 AN: 152200 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00465

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.00214 AC: 537 AN: 251336 AF XY: 0.00223

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.00124

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.00408

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00456 AC: 6668 AN: 1461806 Hom.: 22 Cov.: 33 AF XY: 0.00438 AC XY: 3182 AN XY: 727212

African (AFR) AF: 0.000508 AC: 17 AN: 33480

American (AMR) AF: 0.00150 AC: 67 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.000300 AC: 16 AN: 53408

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5766

European-Non Finnish (NFE) AF: 0.00572 AC: 6365 AN: 1111944

Other (OTH) AF: 0.00326 AC: 197 AN: 60392

GnomAD4 genome AF: 0.00251 AC: 382 AN: 152318 Hom.: 1 Cov.: 32 AF XY: 0.00205 AC XY: 153 AN XY: 74474

African (AFR) AF: 0.000890 AC: 37 AN: 41572

American (AMR) AF: 0.00170 AC: 26 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00465 AC: 316 AN: 68022

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00368 Hom.: 2

Bravo AF: 0.00258

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00500 AC: 43

ExAC AF: 0.00177 AC: 215

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Histidinemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	0.030
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.040	T
MetaSVM	Uncertain	0.30	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		4.8
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.92	P
Vest4		0.80
MVP		0.72
MPC		0.61
ClinPred		0.056	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.67
gMVP		0.73
Mutation Taster		=43/57	disease causing

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: rs61937878; hg19: chr12-96371731;