rs118204109

chr11-119091515-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000190.4(HMBS):c.601C>T(p.Arg201Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000168 in 1,550,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R201Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: HMBS NM_000190.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 2.00

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000190.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 11-119091515-C-T is Pathogenic according to our data. Variant chr11-119091515-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1462.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HMBS	NM_000190.4	c.601C>T	p.Arg201Trp	missense_variant	9/14	ENST00000652429.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HMBS	ENST00000652429.1	c.601C>T	p.Arg201Trp	missense_variant	9/14		NM_000190.4	P3

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152246 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000256 AC: 4 AN: 155962 Hom.: 0 AF XY: 0.0000365 AC XY: 3 AN XY: 82192

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000404

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000885

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000332

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000143 AC: 20 AN: 1397758 Hom.: 0 Cov.: 30 AF XY: 0.0000145 AC XY: 10 AN XY: 689526

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000560

Gnomad4 SAS exome AF: 0.0000126

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000158

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152246 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74386

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000831 Hom.: 0

Bravo AF: 0.0000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 03, 2023	This variant is present in population databases (rs118204109, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 201 of the HMBS protein (p.Arg201Trp). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects HMBS function (PMID: 7962538, 11055586). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HMBS protein function. ClinVar contains an entry for this variant (Variation ID: 1462). This missense change has been observed in individual(s) with acute intermitent porphyria (PMID: 7962538, 8270256, 26075277). It has also been observed to segregate with disease in related individuals. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 15, 2019	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 12372055, 7962538, 8270256, 26075277, 11055586) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 23, 2022	PP3, PP4, PM2, PS3 -

Acute intermittent porphyria Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Dec 18, 2018	The HMBS c.601C>T (p.Arg201Trp) missense variant has been reported in at least four studies in which it was found in a heterozygous state in at least 12 individuals with acute intermittent porphyria or hydroxymethylbilane synthase deficiency.(Lundin et al. 1994; Chen et al. 1994; Floderus et al. 2002; Cerbino et al. 2015). At least seven of these individuals were from one family in which the variant displayed segregation with disease (Lundin et al. 1994). Control data are unavailable for the p.Arg201Trp variant, which is reported at a frequency of 0.000027 in the total population of the Genome Aggregation Database. Functional studies conducted in E. coli indicate the variant form of the protein exhibited reduced enzymatic activity and stability compared to the wild type (Chen et al. 1994). Based on the collective evidence, the p.Arg201Trp variant is classified as pathogenic for hydroxymethylbilane synthase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1994	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.53
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Uncertain	0.34
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A
PrimateAI	Uncertain	0.64	T
REVEL	Pathogenic	0.93
Polyphen		1.0	.;D;D;.;.;.;.;D;.;D;.;D;D
Vest4		0.90, 0.91, 0.88, 0.90, 0.86, 0.91
MutPred		0.92		.;Loss of MoRF binding (P = 0.0825);.;.;.;.;Loss of MoRF binding (P = 0.0825);.;.;.;.;.;.;
MVP		0.98
MPC		1.2
ClinPred		0.99	D
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96

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

Publications

LitVar

Other links and lift over

dbSNP: rs118204109; hg19: chr11-118962225;