Genetic Variant NM_000190.4:c.613-19C>A (chr11-119092106-C-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.613-19C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.26 in 1,609,796 control chromosomes in the GnomAD database, including 57,608 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.25 ( 5233 hom., cov: 32)

Exomes 𝑓: 0.26 ( 52375 hom. )

Consequence

HMBS
NM_000190.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -2.00

Publications

28 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=-0.77).

BP6

Variant 11-119092106-C-A is Benign according to our data. Variant chr11-119092106-C-A is described in ClinVar as Benign. ClinVar VariationId is 255486.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.463 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.613-19C>A	intron	N/A	NP_000181.2
HMBS	NM_001425056.1		c.613-19C>A	intron	N/A	NP_001411985.1
HMBS	NM_001425057.1		c.595-19C>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.613-19C>A	intron	N/A	ENSP00000498786.1	P08397-1
HMBS	ENST00000392841.1	TSL:1	c.562-19C>A	intron	N/A	ENSP00000376584.1	P08397-2
HMBS	ENST00000545621.5	TSL:1	n.*508-19C>A	intron	N/A	ENSP00000444849.1	F5H4X2

Frequencies

GnomAD3 genomes

AF:

0.254

AC:

38667

AN:

152008

Hom.:

5220

Cov.:

show subpopulations

Gnomad AFR

AF:

0.183

Gnomad AMI

AF:

0.226

Gnomad AMR

AF:

0.317

Gnomad ASJ

AF:

0.307

Gnomad EAS

AF:

0.479

Gnomad SAS

AF:

0.328

Gnomad FIN

AF:

0.317

Gnomad MID

AF:

0.222

Gnomad NFE

AF:

0.249

Gnomad OTH

AF:

0.265

GnomAD2 exomes

AF:

0.301

AC:

75561

AN:

251102

AF XY:

0.298

show subpopulations

Gnomad AFR exome

AF:

0.178

Gnomad AMR exome

AF:

0.406

Gnomad ASJ exome

AF:

0.314

Gnomad EAS exome

AF:

0.485

Gnomad FIN exome

AF:

0.320

Gnomad NFE exome

AF:

0.248

Gnomad OTH exome

AF:

0.281

GnomAD4 exome

AF:

0.260

AC:

379514

AN:

1457670

Hom.:

52375

Cov.:

AF XY:

0.263

AC XY:

190491

AN XY:

725336

show subpopulations

African (AFR)

AF:

0.177

AC:

5914

AN:

33340

American (AMR)

AF:

0.396

AC:

17678

AN:

44684

Ashkenazi Jewish (ASJ)

AF:

0.314

AC:

8191

AN:

26094

East Asian (EAS)

AF:

0.482

AC:

19132

AN:

39664

South Asian (SAS)

AF:

0.317

AC:

27289

AN:

86124

European-Finnish (FIN)

AF:

0.316

AC:

16847

AN:

53352

Middle Eastern (MID)

AF:

0.262

AC:

1395

AN:

5322

European-Non Finnish (NFE)

AF:

0.241

AC:

266831

AN:

1108870

Other (OTH)

AF:

0.270

AC:

16237

AN:

60220

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

13249

26498

39746

52995

66244

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9192

18384

27576

36768

45960

<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:

0.254

AC:

38711

AN:

152126

Hom.:

5233

Cov.:

AF XY:

0.263

AC XY:

19566

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.184

AC:

7626

AN:

41520

American (AMR)

AF:

0.317

AC:

4845

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.307

AC:

1067

AN:

3472

East Asian (EAS)

AF:

0.479

AC:

2475

AN:

5170

South Asian (SAS)

AF:

0.327

AC:

1576

AN:

4818

European-Finnish (FIN)

AF:

0.317

AC:

3346

AN:

10562

Middle Eastern (MID)

AF:

0.221

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.249

AC:

16935

AN:

67996

Other (OTH)

AF:

0.271

AC:

571

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1435

2870

4305

5740

7175

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

408

816

1224

1632

2040

<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:

0.248

Hom.:

9081

Bravo

AF:

0.252

Asia WGS

AF:

0.389

AC:

1355

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

not provided (2)

Acute intermittent porphyria (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

6.6

(source)

DANN

Benign

0.78

PhyloP100

-2.0

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)

0.030

Details are displayed if max score is > 0.2

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

Publications

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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