Genetic Variant HMBS:c.88-14G>A (chr11-119088621-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000190.4(HMBS):c.88-14G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.56 in 1,605,040 control chromosomes in the GnomAD database, including 256,196 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.61 ( 29024 hom., cov: 31)

Exomes 𝑓: 0.55 ( 227172 hom. )

Consequence

HMBS
NM_000190.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.286

Publications

26 publications found

Variant links:

Genes affected

HMBS (HGNC:4982): (hydroxymethylbilane synthase) This gene encodes a member of the hydroxymethylbilane synthase superfamily. The encoded protein is the third enzyme of the heme biosynthetic pathway and catalyzes the head to tail condensation of four porphobilinogen molecules into the linear hydroxymethylbilane. Mutations in this gene are associated with the autosomal dominant disease acute intermittent porphyria. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

HMBS Gene-Disease associations (from GenCC):

acute intermittent porphyria
Inheritance: AD, SD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

HMBS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 11-119088621-G-A is Benign according to our data. Variant chr11-119088621-G-A is described in ClinVar as Benign. ClinVar VariationId is 255487.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.745 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000190.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HMBS	NM_000190.4	MANE Select	c.88-14G>A	intron	N/A	NP_000181.2
HMBS	NM_001425056.1		c.88-14G>A	intron	N/A	NP_001411985.1
HMBS	NM_001425057.1		c.88-14G>A	intron	N/A	NP_001411986.1	A0A3F2YNY7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HMBS	ENST00000652429.1	MANE Select	c.88-14G>A	intron	N/A	ENSP00000498786.1	P08397-1
HMBS	ENST00000392841.1	TSL:1	c.37-14G>A	intron	N/A	ENSP00000376584.1	P08397-2
HMBS	ENST00000545621.5	TSL:1	n.88-14G>A	intron	N/A	ENSP00000444849.1	F5H4X2

Frequencies

GnomAD3 genomes

AF:

0.608

AC:

92329

AN:

151916

Hom.:

28992

Cov.:

show subpopulations

Gnomad AFR

AF:

0.752

Gnomad AMI

AF:

0.637

Gnomad AMR

AF:

0.680

Gnomad ASJ

AF:

0.569

Gnomad EAS

AF:

0.283

Gnomad SAS

AF:

0.501

Gnomad FIN

AF:

0.459

Gnomad MID

AF:

0.589

Gnomad NFE

AF:

0.561

Gnomad OTH

AF:

0.604

GnomAD2 exomes

AF:

0.560

AC:

140916

AN:

251432

AF XY:

0.552

show subpopulations

Gnomad AFR exome

AF:

0.752

Gnomad AMR exome

AF:

0.725

Gnomad ASJ exome

AF:

0.574

Gnomad EAS exome

AF:

0.278

Gnomad FIN exome

AF:

0.468

Gnomad NFE exome

AF:

0.557

Gnomad OTH exome

AF:

0.569

GnomAD4 exome

AF:

0.555

AC:

805838

AN:

1453006

Hom.:

227172

Cov.:

AF XY:

0.553

AC XY:

399884

AN XY:

723366

show subpopulations

African (AFR)

AF:

0.754

AC:

25126

AN:

33314

American (AMR)

AF:

0.720

AC:

32210

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.571

AC:

14892

AN:

26078

East Asian (EAS)

AF:

0.268

AC:

10649

AN:

39674

South Asian (SAS)

AF:

0.518

AC:

44592

AN:

86136

European-Finnish (FIN)

AF:

0.471

AC:

25141

AN:

53414

Middle Eastern (MID)

AF:

0.580

AC:

3318

AN:

5724

European-Non Finnish (NFE)

AF:

0.558

AC:

616199

AN:

1103856

Other (OTH)

AF:

0.561

AC:

33711

AN:

60100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

17836

35673

53509

71346

89182

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17142

34284

51426

68568

85710

<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:

0.608

AC:

92412

AN:

152034

Hom.:

29024

Cov.:

AF XY:

0.602

AC XY:

44729

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.752

AC:

31176

AN:

41484

American (AMR)

AF:

0.679

AC:

10379

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.569

AC:

1977

AN:

3472

East Asian (EAS)

AF:

0.283

AC:

1458

AN:

5154

South Asian (SAS)

AF:

0.501

AC:

2415

AN:

4822

European-Finnish (FIN)

AF:

0.459

AC:

4857

AN:

10576

Middle Eastern (MID)

AF:

0.588

AC:

173

AN:

294

European-Non Finnish (NFE)

AF:

0.561

AC:

38130

AN:

67944

Other (OTH)

AF:

0.603

AC:

1267

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1787

3575

5362

7150

8937

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

748

1496

2244

2992

3740

<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:

0.583

Hom.:

37384

Bravo

AF:

0.631

Asia WGS

AF:

0.416

AC:

1444

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Acute intermittent porphyria (3)

not specified (3)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.29

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over