11-119085172-CTTTTTTTTTTTTTTTTTTTTTT-CTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTT

Variant names:

• chr11-119085172-C-CTTTTTTTTTTTTTTTTTT
• rs549270240
• NM_000190.4:c.33+118_33+135dupTTTTTTTTTTTTTTTTTT

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS2_Supporting

The NM_000190.4(HMBS):​c.33+118_33+135dupTTTTTTTTTTTTTTTTTT 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 0.000090 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000060 (3 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: Orphanet, Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BS2: High AC in GnomAd4 at 6 AD,SD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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+118_33+135dupTTTTTTTTTTTTTTTTTT		intron	N/A	NP_000181.2
	HMBS	NM_001425056.1		c.33+118_33+135dupTTTTTTTTTTTTTTTTTT		intron	N/A	NP_001411985.1
	HMBS	NM_001425057.1		c.33+118_33+135dupTTTTTTTTTTTTTTTTTT		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+107insTTTTTTTTTTTTTTTTTT		intron	N/A	ENSP00000498786.1	P08397-1
	HMBS	ENST00000545621.5	TSL:1	n.33+106_33+107insTTTTTTTTTTTTTTTTTT		intron	N/A	ENSP00000444849.1	F5H4X2
	HMBS	ENST00000545901.5	TSL:1	n.186+106_186+107insTTTTTTTTTTTTTTTTTT		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000899 AC: 6 AN: 66768 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000544

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: 0.000138

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000600 AC: 44 AN: 732828 Hom.: 3 Cov.: 0 AF XY: 0.0000745 AC XY: 27 AN XY: 362474

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

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

Ashkenazi Jewish (ASJ) AF: 0.0000964 AC: 1 AN: 10372

East Asian (EAS) AF: 0.000256 AC: 2 AN: 7824

South Asian (SAS) AF: 0.000179 AC: 9 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: 0.0000522 AC: 31 AN: 593390

Other (OTH) AF: 0.0000362 AC: 1 AN: 27606

GnomAD4 genome AF: 0.0000898 AC: 6 AN: 66804 Hom.: 0 Cov.: 0 AF XY: 0.000102 AC XY: 3 AN XY: 29540

African (AFR) AF: 0.0000543 AC: 1 AN: 18402

American (AMR) AF: 0.00 AC: 0 AN: 4796

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 1404

South Asian (SAS) AF: 0.00 AC: 0 AN: 1308

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 74

European-Non Finnish (NFE) AF: 0.000138 AC: 5 AN: 36234

Other (OTH) AF: 0.00 AC: 0 AN: 858

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs549270240;

hg19: chr11-118955882;