rs1799993

Variant names:

• chr11-119087417-C-A
• rs1799993
• NM_000190.4:c.34-838C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000190.4(HMBS):​c.34-838C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.459 in 151,936 control chromosomes in the GnomAD database, including 17,599 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.46 (17597 hom., cov: 31)
  • Exomes 𝑓: 0.29 (2 hom.)
• Consequence: HMBS NM_000190.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.106
• Publications: 28 publications found

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

ENSG00000298165 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.671 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMBS	NM_000190.4	MANE Select	c.34-838C>A		intron	N/A	NP_000181.2
	HMBS	NM_001425056.1		c.34-838C>A		intron	N/A	NP_001411985.1
	HMBS	NM_001425057.1		c.34-838C>A		intron	N/A	NP_001411986.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMBS	ENST00000652429.1	MANE Select	c.34-838C>A		intron	N/A	ENSP00000498786.1
	HMBS	ENST00000545621.5	TSL:1	n.34-838C>A		intron	N/A	ENSP00000444849.1
	HMBS	ENST00000545901.5	TSL:1	n.187-838C>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.459 AC: 69659 AN: 151786 Hom.: 17572 Cov.: 31

Gnomad AFR AF: 0.677

Gnomad AMI AF: 0.421

Gnomad AMR AF: 0.375

Gnomad ASJ AF: 0.406

Gnomad EAS AF: 0.184

Gnomad SAS AF: 0.348

Gnomad FIN AF: 0.284

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.404

Gnomad OTH AF: 0.461

GnomAD4 exome AF: 0.294 AC: 10 AN: 34 Hom.: 2 AF XY: 0.200 AC XY: 4 AN XY: 20

African (AFR) AC: 0 AN: 0

American (AMR) AF: 0.500 AC: 1 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.308 AC: 8 AN: 26

Other (OTH) AF: 0.500 AC: 1 AN: 2

GnomAD4 genome AF: 0.459 AC: 69724 AN: 151902 Hom.: 17597 Cov.: 31 AF XY: 0.450 AC XY: 33364 AN XY: 74222

African (AFR) AF: 0.677 AC: 28050 AN: 41408

American (AMR) AF: 0.375 AC: 5723 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.406 AC: 1410 AN: 3470

East Asian (EAS) AF: 0.184 AC: 952 AN: 5168

South Asian (SAS) AF: 0.348 AC: 1676 AN: 4822

European-Finnish (FIN) AF: 0.284 AC: 2988 AN: 10526

Middle Eastern (MID) AF: 0.435 AC: 127 AN: 292

European-Non Finnish (NFE) AF: 0.404 AC: 27443 AN: 67920

Other (OTH) AF: 0.462 AC: 973 AN: 2108

Alfa AF: 0.427 Hom.: 19642

Bravo AF: 0.474

Asia WGS AF: 0.297 AC: 1031 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.95
DANN	Benign	0.67
PhyloP100		-0.11
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1799993; hg19: chr11-118958127;