rs118204105

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5

The NM_000190.4(HMBS):​c.100C>A​(p.Gln34Lys) variant causes a missense 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 (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q34P) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

HMBS
NM_000190.4 missense

Scores

14
3
1

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 6.97
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM1
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000190.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.991
PP5
Variant 11-119088647-C-A is Pathogenic according to our data. Variant chr11-119088647-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 1455.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
HMBSNM_000190.4 linkuse as main transcriptc.100C>A p.Gln34Lys missense_variant 3/14 ENST00000652429.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
HMBSENST00000652429.1 linkuse as main transcriptc.100C>A p.Gln34Lys missense_variant 3/14 NM_000190.4 P3P08397-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Acute intermittent porphyria Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMSep 01, 1992- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.97
BayesDel_addAF
Pathogenic
0.58
D
BayesDel_noAF
Pathogenic
0.60
CADD
Pathogenic
30
DANN
Uncertain
0.98
DEOGEN2
Pathogenic
1.0
.;D;.;.;D;.;.;D;.;.;.;.;.
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.90
FATHMM_MKL
Pathogenic
0.98
D
M_CAP
Pathogenic
0.67
D
MetaRNN
Pathogenic
0.99
D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
0.90
D
MutationAssessor
Pathogenic
4.5
.;H;.;.;.;.;H;.;.;.;.;.;.
MutationTaster
Benign
1.0
A;A;A;A;A;A;A
PrimateAI
Uncertain
0.67
T
PROVEAN
Uncertain
-3.7
.;D;D;D;D;.;D;D;.;D;D;D;.
REVEL
Pathogenic
0.97
Sift
Pathogenic
0.0
.;D;D;D;D;.;D;D;.;D;D;D;.
Sift4G
Pathogenic
0.0
.;D;D;D;D;.;D;D;.;D;D;D;.
Polyphen
1.0, 1.0
.;D;.;.;.;.;.;D;.;.;.;.;.
Vest4
0.99, 1.0, 0.96, 0.98, 0.97, 0.99
MutPred
0.99
Gain of catalytic residue at Q34 (P = 0.0293);Gain of catalytic residue at Q34 (P = 0.0293);.;.;Gain of catalytic residue at Q34 (P = 0.0293);.;Gain of catalytic residue at Q34 (P = 0.0293);.;.;.;.;.;.;
MVP
0.98
MPC
1.1
ClinPred
1.0
D
GERP RS
5.0
Varity_R
0.99

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs118204105; hg19: chr11-118959357; API