chr11-119085068-T-A

Variant names:

• chr11-119085068-T-A
• NM_000190.4:c.33+2T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_000190.4(HMBS):​c.33+2T>A variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: HMBS NM_000190.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.24
• Publications: 1 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, Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp

ACMG classification

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

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.17127071 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.3, offset of 15, new splice context is: ccgGTgacc. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-119085068-T-A is Pathogenic according to our data. Variant chr11-119085068-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 3721099.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.33+2T>A		splice_donor intron	N/A	NP_000181.2
	HMBS	NM_001425052.1		c.-108T>A		5_prime_UTR	Exon 1 of 14	NP_001411981.1	P08397-2
	HMBS	NM_001425053.1		c.-84T>A		5_prime_UTR	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+2T>A		splice_donor intron	N/A	ENSP00000498786.1	P08397-1
	HMBS	ENST00000545621.5	TSL:1	n.33+2T>A		splice_donor intron	N/A	ENSP00000444849.1	F5H4X2
	HMBS	ENST00000545901.5	TSL:1	n.186+2T>A		splice_donor intron	N/A

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 43

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	29
DANN	Uncertain	0.99
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.94	D
PhyloP100		2.2
GERP RS		5.9
PromoterAI		-0.63	Under-expression
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=6/294	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.98		Position offset: -2

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

Other links and lift over

hg19: chr11-118955778;