11-119085067-G-A

Variant names:

• chr11-119085067-G-A
• rs1565750784
• NM_000190.4:c.33+1G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_001425052.1(HMBS):​c.-109G>A variant causes a 5 prime UTR premature start codon gain 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 (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: HMBS NM_001425052.1 5_prime_UTR_premature_start_codon_gain
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.56
• Publications: 2 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: Genomics England PanelApp, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 11-119085067-G-A is Pathogenic according to our data. Variant chr11-119085067-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1441.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001425052.1. 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.33+1G>A		splice_donor intron	N/A	NP_000181.2
	HMBS	NM_001425052.1		c.-109G>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 14	NP_001411981.1	P08397-2
	HMBS	NM_001425053.1		c.-85G>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 14	NP_001411982.1	P08397-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMBS	ENST00000652429.1	MANE Select	c.33+1G>A		splice_donor intron	N/A	ENSP00000498786.1	P08397-1
	HMBS	ENST00000545621.5	TSL:1	n.33+1G>A		splice_donor intron	N/A	ENSP00000444849.1	F5H4X2
	HMBS	ENST00000545901.5	TSL:1	n.186+1G>A		splice_donor intron	N/A

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 43

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)
1	-	-	Porphyria, acute intermittent, nonerythroid variant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Uncertain	0.96	D
PhyloP100		4.6
GERP RS		5.9
PromoterAI		-0.59	Under-expression
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Mutation Taster		=2/298	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.98		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1565750784; hg19: chr11-118955777; COSMIC: COSV53828220; COSMIC: COSV53828220;