NM_000190.4:c.33+109_33+135dupTTTTTTTTTTTTTTTTTTTTTTTTTTT

Variant names:

• chr11-119085172-C-CTTTTTTTTTTTTTTTTTTTTTTTTTTT
• rs549270240
• NM_000190.4:c.33+109_33+135dupTTTTTTTTTTTTTTTTTTTTTTTTTTT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_000190.4(HMBS):​c.33+109_33+135dupTTTTTTTTTTTTTTTTTTTTTTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000030 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HMBS NM_000190.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.497
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

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+109_33+135dupTTTTTTTTTTTTTTTTTTTTTTTTTTT		intron	N/A	NP_000181.2
	HMBS	NM_001425056.1		c.33+109_33+135dupTTTTTTTTTTTTTTTTTTTTTTTTTTT		intron	N/A	NP_001411985.1
	HMBS	NM_001425057.1		c.33+109_33+135dupTTTTTTTTTTTTTTTTTTTTTTTTTTT		intron	N/A	NP_001411986.1	A0A3F2YNY7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMBS	ENST00000652429.1	MANE Select	c.33+106_33+107insTTTTTTTTTTTTTTTTTTTTTTTTTTT		intron	N/A	ENSP00000498786.1	P08397-1
	HMBS	ENST00000545621.5	TSL:1	n.33+106_33+107insTTTTTTTTTTTTTTTTTTTTTTTTTTT		intron	N/A	ENSP00000444849.1	F5H4X2
	HMBS	ENST00000545901.5	TSL:1	n.186+106_186+107insTTTTTTTTTTTTTTTTTTTTTTTTTTT		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000300 AC: 2 AN: 66768 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

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: 0.0000552

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 732832 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 362476

African (AFR) AF: 0.00 AC: 0 AN: 18384

American (AMR) AF: 0.00 AC: 0 AN: 11818

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10372

East Asian (EAS) AF: 0.00 AC: 0 AN: 7824

South Asian (SAS) AF: 0.00 AC: 0 AN: 50144

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 11370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1920

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 593392

Other (OTH) AF: 0.00 AC: 0 AN: 27608

GnomAD4 genome AF: 0.0000300 AC: 2 AN: 66768 Hom.: 0 Cov.: 0 AF XY: 0.0000339 AC XY: 1 AN XY: 29496

African (AFR) AF: 0.00 AC: 0 AN: 18368

American (AMR) AF: 0.00 AC: 0 AN: 4790

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2142

East Asian (EAS) AF: 0.00 AC: 0 AN: 1402

South Asian (SAS) AF: 0.00 AC: 0 AN: 1312

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1126

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 80

European-Non Finnish (NFE) AF: 0.0000552 AC: 2 AN: 36236

Other (OTH) AF: 0.00 AC: 0 AN: 852

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.50

Splicing

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

Other links and lift over

dbSNP: rs549270240; hg19: chr11-118955882;