rs118204117

Variant names:

• chr11-119092958-G-A
• rs118204117
• NM_000190.4:c.849G>A
• HMBS p.Trp283*

Your query was ambiguous. Multiple possible variants found:

• chr11-119092958-G-A
• chr11-119092958-G-C

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_Very_Strong

The NM_000190.4(HMBS):​c.849G>A​(p.Trp283*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000516944: Published functional studies demonstrate that the variant results in significantly reduced enzyme activity (PMID:7962538)". Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HMBS NM_000190.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 4.97
• Publications: 14 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 22 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000516944: Published functional studies demonstrate that the variant results in significantly reduced enzyme activity (PMID: 7962538)
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-119092958-G-A is Pathogenic according to our data. Variant chr11-119092958-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.849G>A	p.Trp283*	stop_gained	Exon 13 of 14	NP_000181.2
	HMBS	NM_001425056.1		c.840G>A	p.Trp280*	stop_gained	Exon 13 of 14	NP_001411985.1
	HMBS	NM_001425057.1		c.831G>A	p.Trp277*	stop_gained	Exon 13 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.849G>A	p.Trp283*	stop_gained	Exon 13 of 14	ENSP00000498786.1	P08397-1
	HMBS	ENST00000392841.1	TSL:1	c.798G>A	p.Trp266*	stop_gained	Exon 13 of 14	ENSP00000376584.1	P08397-2
	HMBS	ENST00000933410.1		c.840G>A	p.Trp280*	stop_gained	Exon 13 of 14	ENSP00000603469.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	not provided (3)
1	-	-	Acute intermittent porphyria (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	40
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Uncertain	0.96	D
PhyloP100		5.0
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: rs118204117;

hg19: chr11-118963668;