rs1057518886

Variant names:

• chr11-119090042-AC-A
• rs1057518886
• NM_000190.4:c.400delC

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000190.4(HMBS):​c.400delC​(p.Leu134fs) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HMBS NM_000190.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.83
• Publications: 0 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: AD, SD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-119090042-AC-A is Pathogenic according to our data. Variant chr11-119090042-AC-A is described in ClinVar as Pathogenic. ClinVar VariationId is 374084.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMBS	NM_000190.4	MANE Select	c.400delC	p.Leu134fs	frameshift	Exon 7 of 14	NP_000181.2
	HMBS	NM_001425056.1		c.400delC	p.Leu134fs	frameshift	Exon 7 of 14	NP_001411985.1
	HMBS	NM_001425057.1		c.382delC	p.Leu128fs	frameshift	Exon 7 of 14	NP_001411986.1	A0A3F2YNY7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMBS	ENST00000652429.1	MANE Select	c.400delC	p.Leu134fs	frameshift	Exon 7 of 14	ENSP00000498786.1	P08397-1
	HMBS	ENST00000392841.1	TSL:1	c.349delC	p.Leu117fs	frameshift	Exon 7 of 14	ENSP00000376584.1	P08397-2
	HMBS	ENST00000545621.5	TSL:1	n.*295delC		non_coding_transcript_exon	Exon 7 of 10	ENSP00000444849.1	F5H4X2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Abdominal pain;C0015967:Fever;C0042963:Vomiting;C0085633:Emotional lability;C3665386:Visual loss (1)
1	-	-	Acute intermittent porphyria (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.8
Mutation Taster		=0/200	disease causing (ClinVar)

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.

Other links and lift over

dbSNP: rs1057518886;

hg19: chr11-118960752;