dbSNP rs141634423: HAL:c.1287+2T>C (chr12-95983909-A-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PVS1_Moderate

The NM_002108.4(HAL):c.1287+2T>C variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000244 in 1,467,544 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as association (★).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00025 ( 0 hom. )

Consequence

HAL
NM_002108.4 splice_donor, intron

Scores

Splicing: ADA: 0.9732

Clinical Significance

association criteria provided, single submitter O:1

Conservation

PhyloP100: 8.85

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.041033436 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6, offset of 46, new splice context is: ctgGTaatt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HAL	NM_002108.4 link	c.1287+2T>C		splice_donor_variant, intron_variant	Intron 15 of 20	ENST00000261208.8	NP_002099.1	P42357-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HAL	ENST00000261208.8 link	c.1287+2T>C		splice_donor_variant, intron_variant	Intron 15 of 20	1	NM_002108.4	ENSP00000261208.3		P42357-1

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000200

AC:

AN:

250290

AF XY:

0.000185

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000397

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000255

AC:

335

AN:

1315306

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

160

AN XY:

662202

show subpopulations

Gnomad4 AFR exome

AF:

0.0000326

AC:

AN:

30628

Gnomad4 AMR exome

AF:

0.0000449

AC:

AN:

44514

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

25184

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39054

Gnomad4 SAS exome

AF:

0.0000481

AC:

AN:

83220

Gnomad4 FIN exome

AF:

0.0000751

AC:

AN:

53240

Gnomad4 NFE exome

AF:

0.000325

AC:

318

AN:

979744

Gnomad4 Remaining exome

AF:

0.000108

AC:

AN:

55364

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000151

AC:

AN:

152238

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.0000482

AC:

0.0000482486

AN:

0.0000482486

Gnomad4 AMR

AF:

0.00

AC:

AN:

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.000207

AC:

0.000206868

AN:

0.000206868

Gnomad4 FIN

AF:

0.0000941

AC:

0.0000940911

AN:

0.0000940911

Gnomad4 NFE

AF:

0.000265

AC:

0.000264558

AN:

0.000264558

Gnomad4 OTH

AF:

0.000478

AC:

0.000477555

AN:

0.000477555

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000305

Hom.:

Bravo

AF:

0.000227

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000214

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000237

ClinVar

Significance: association

Submissions summary: Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Increased histidine

Other:1

Nov 15, 2015

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance:association

Review Status:criteria provided, single submitter

Collection Method:research

Three heterozygous loss-of-function variants in HAL were found in 24/1152 African American individuals, in association with elevated serum histidine levels. Histidine level is a potential predictor of cardiovascular risk. Thus, loss-of-function variants in HAL may modify cardiovascular risk. Findings were replicated in a European American cohort. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.060

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

0.99

GERP RS

5.3

Mutation Taster

=0/100

disease causing

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.97

SpliceAI score (max)

0.96

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.70

Position offset: -44

DS_DL_spliceai

0.96

Position offset: 2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over