12-95992778-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002108.4(HAL):c.617G>A(p.Arg206Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,460,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R206T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: HAL NM_002108.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.77

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32722378).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HAL	NM_002108.4	c.617G>A	p.Arg206Lys	missense_variant	9/21	ENST00000261208.8
HAL	NM_001258334.2	c.617G>A	p.Arg206Lys	missense_variant	9/20
HAL	NM_001258333.2	c.-8G>A		5_prime_UTR_variant	8/20
HAL	XM_011538249.3			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HAL	ENST00000261208.8	c.617G>A	p.Arg206Lys	missense_variant	9/21	1	NM_002108.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000318 AC: 8 AN: 251484 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1460528 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 726654

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Uncertain	-0.030
Cadd	Benign	20
Dann	Benign	0.95
DEOGEN2	Benign	0.30	T;.;T;.
Eigen	Benign	-0.13
Eigen_PC	Benign	0.028
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.79	T;T;T;T
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.33	T;T;T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	1.7	L;L;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.8	N;N;N;N
REVEL	Uncertain	0.44
Sift	Benign	0.76	T;T;T;T
Sift4G	Benign	0.77	T;T;T;.
Polyphen		0.020	B;.;.;.
Vest4		0.51
MutPred		0.60		Gain of catalytic residue at L202 (P = 3e-04);Gain of catalytic residue at L202 (P = 3e-04);.;.;
MVP		0.58
MPC		0.16
ClinPred		0.13	T
GERP RS		4.8
Varity_R		0.39
gMVP		0.86

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: rs121434327; hg19: chr12-96386556;