dbSNP rs1006195: HMBS:c.34-96G>T (chr11-119088159-G-T) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_000190.4(HMBS):c.34-96G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.375 in 1,584,156 control chromosomes in the GnomAD database, including 115,117 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.32 ( 8542 hom., cov: 33)

Exomes 𝑓: 0.38 ( 106575 hom. )

Consequence

HMBS
NM_000190.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.104

Publications

27 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 -16 ACMG points.

BP6

Variant 11-119088159-G-T is Benign according to our data. Variant chr11-119088159-G-T is described in ClinVar as Benign. ClinVar VariationId is 1246575.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.396 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.34-96G>T	intron	N/A	NP_000181.2
HMBS	NM_001425056.1		c.34-96G>T	intron	N/A	NP_001411985.1
HMBS	NM_001425057.1		c.34-96G>T	intron	N/A	NP_001411986.1	A0A3F2YNY7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HMBS	ENST00000652429.1	MANE Select	c.34-96G>T	intron	N/A	ENSP00000498786.1	P08397-1
HMBS	ENST00000392841.1	TSL:1	c.-19+81G>T	intron	N/A	ENSP00000376584.1	P08397-2
HMBS	ENST00000545621.5	TSL:1	n.34-96G>T	intron	N/A	ENSP00000444849.1	F5H4X2

Frequencies

GnomAD3 genomes

AF:

0.325

AC:

49416

AN:

152090

Hom.:

8547

Cov.:

show subpopulations

Gnomad AFR

AF:

0.231

Gnomad AMI

AF:

0.423

Gnomad AMR

AF:

0.289

Gnomad ASJ

AF:

0.386

Gnomad EAS

AF:

0.165

Gnomad SAS

AF:

0.361

Gnomad FIN

AF:

0.283

Gnomad MID

AF:

0.405

Gnomad NFE

AF:

0.400

Gnomad OTH

AF:

0.361

GnomAD4 exome

AF:

0.380

AC:

543940

AN:

1431948

Hom.:

106575

Cov.:

AF XY:

0.381

AC XY:

272062

AN XY:

714036

show subpopulations

African (AFR)

AF:

0.223

AC:

7350

AN:

32904

American (AMR)

AF:

0.242

AC:

10780

AN:

44628

Ashkenazi Jewish (ASJ)

AF:

0.394

AC:

10220

AN:

25928

East Asian (EAS)

AF:

0.144

AC:

5704

AN:

39480

South Asian (SAS)

AF:

0.371

AC:

31631

AN:

85284

European-Finnish (FIN)

AF:

0.290

AC:

15420

AN:

53180

Middle Eastern (MID)

AF:

0.374

AC:

2045

AN:

5466

European-Non Finnish (NFE)

AF:

0.404

AC:

438945

AN:

1085748

Other (OTH)

AF:

0.368

AC:

21845

AN:

59330

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

17525

35050

52576

70101

87626

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13242

26484

39726

52968

66210

<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:

0.325

AC:

49417

AN:

152208

Hom.:

8542

Cov.:

AF XY:

0.319

AC XY:

23734

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.231

AC:

9590

AN:

41496

American (AMR)

AF:

0.288

AC:

4409

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.386

AC:

1341

AN:

3470

East Asian (EAS)

AF:

0.165

AC:

857

AN:

5186

South Asian (SAS)

AF:

0.360

AC:

1741

AN:

4830

European-Finnish (FIN)

AF:

0.283

AC:

3005

AN:

10608

Middle Eastern (MID)

AF:

0.398

AC:

117

AN:

294

European-Non Finnish (NFE)

AF:

0.400

AC:

27204

AN:

68002

Other (OTH)

AF:

0.363

AC:

767

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1708

3417

5125

6834

8542

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

502

1004

1506

2008

2510

<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:

0.359

Hom.:

4564

Bravo

AF:

0.319

Asia WGS

AF:

0.271

AC:

940

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

(source)

DANN

Benign

0.75

PhyloP100

-0.10

PromoterAI

0.047

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.26

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.26

Position offset: 20

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

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