rs61937878

chr12-95977953-C-T

Variant summary

Our verdict is Benign. Variant got -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

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.040305644).
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HAL	NM_002108.4	c.1645G>A	p.Val549Met	missense_variant	18/21	ENST00000261208.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HAL	ENST00000261208.8	c.1645G>A	p.Val549Met	missense_variant	18/21	1	NM_002108.4	P1

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

GnomAD3 exomes AF: 0.00214 AC: 537 AN: 251336 Hom.: 2 AF XY: 0.00223 AC XY: 303 AN XY: 135866

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 SAS 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

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.00150

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000300

Gnomad4 NFE exome AF: 0.00572

Gnomad4 OTH exome AF: 0.00326

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

Gnomad4 AFR AF: 0.000890

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00465

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00384 Hom.: 0

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

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Histidinemia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

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;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.040	T;T;T
MetaSVM	Uncertain	0.30	D
MutationAssessor	Pathogenic	3.3	M;.;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.9	D;D;D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.0060	D;D;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs61937878; hg19: chr12-96371731;