chr11-119085172-CTTTTTTTTTTT-C

Variant names:

• chr11-119085172-CTTTTTTTTTTT-C
• rs549270240
• NM_000190.4:c.33+125_33+135delTTTTTTTTTTT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_000190.4(HMBS):​c.33+125_33+135delTTTTTTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0124 in 798,278 control chromosomes in the GnomAD database, including 28 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_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 0.010 (11 hom., cov: 0)
  • Exomes 𝑓: 0.013 (17 hom.)
• Consequence: HMBS NM_000190.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.83
• 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: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.01 (671/66818) while in subpopulation NFE AF = 0.0138 (501/36242). AF 95% confidence interval is 0.0128. There are 11 homozygotes in GnomAd4. There are 272 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 671 AD,SD gene.

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+125_33+135delTTTTTTTTTTT		intron	N/A	NP_000181.2
	HMBS	NM_001425056.1		c.33+125_33+135delTTTTTTTTTTT		intron	N/A	NP_001411985.1
	HMBS	NM_001425057.1		c.33+125_33+135delTTTTTTTTTTT		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+107_33+117delTTTTTTTTTTT		intron	N/A	ENSP00000498786.1	P08397-1
	HMBS	ENST00000545621.5	TSL:1	n.33+107_33+117delTTTTTTTTTTT		intron	N/A	ENSP00000444849.1	F5H4X2
	HMBS	ENST00000545901.5	TSL:1	n.186+107_186+117delTTTTTTTTTTT		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0100 AC: 671 AN: 66782 Hom.: 11 Cov.: 0

Gnomad AFR AF: 0.00572

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00855

Gnomad ASJ AF: 0.000467

Gnomad EAS AF: 0.00214

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00533

Gnomad MID AF: 0.0250

Gnomad NFE AF: 0.0138

Gnomad OTH AF: 0.0141

GnomAD4 exome AF: 0.0127 AC: 9258 AN: 731460 Hom.: 17 AF XY: 0.0122 AC XY: 4427 AN XY: 361808

African (AFR) AF: 0.0450 AC: 817 AN: 18142

American (AMR) AF: 0.0119 AC: 140 AN: 11770

Ashkenazi Jewish (ASJ) AF: 0.00174 AC: 18 AN: 10360

East Asian (EAS) AF: 0.0109 AC: 85 AN: 7810

South Asian (SAS) AF: 0.00124 AC: 62 AN: 50108

European-Finnish (FIN) AF: 0.00484 AC: 55 AN: 11358

Middle Eastern (MID) AF: 0.00939 AC: 18 AN: 1916

European-Non Finnish (NFE) AF: 0.0130 AC: 7685 AN: 592444

Other (OTH) AF: 0.0137 AC: 378 AN: 27552

GnomAD4 genome AF: 0.0100 AC: 671 AN: 66818 Hom.: 11 Cov.: 0 AF XY: 0.00921 AC XY: 272 AN XY: 29548

African (AFR) AF: 0.00571 AC: 105 AN: 18404

American (AMR) AF: 0.00854 AC: 41 AN: 4800

Ashkenazi Jewish (ASJ) AF: 0.000467 AC: 1 AN: 2142

East Asian (EAS) AF: 0.00214 AC: 3 AN: 1404

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

European-Finnish (FIN) AF: 0.00533 AC: 6 AN: 1126

Middle Eastern (MID) AF: 0.0270 AC: 2 AN: 74

European-Non Finnish (NFE) AF: 0.0138 AC: 501 AN: 36242

Other (OTH) AF: 0.0140 AC: 12 AN: 858

Alfa AF: 0.00 Hom.: 67

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.8
Mutation Taster		=100/0	polymorphism

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;