11-119085172-CTTTTTTTTTTTTTTTTTTTTTT-CTTTTTTTTTT

Variant names:

• chr11-119085172-CTTTTTTTTTTTT-C
• rs549270240
• NM_000190.4:c.33+124_33+135delTTTTTTTTTTTT

Variant summary

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

The NM_000190.4(HMBS):​c.33+124_33+135delTTTTTTTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00458 in 798,458 control chromosomes in the GnomAD database, including 1 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 0.00097 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0049 (1 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 sas. GnomAd4 allele frequency = 0.000973 (65/66808) while in subpopulation SAS AF = 0.00306 (4/1308). AF 95% confidence interval is 0.00104. There are 0 homozygotes in GnomAd4. There are 32 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 65 SD,AD 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+124_33+135delTTTTTTTTTTTT		intron	N/A	NP_000181.2
	HMBS	NM_001425056.1		c.33+124_33+135delTTTTTTTTTTTT		intron	N/A	NP_001411985.1
	HMBS	NM_001425057.1		c.33+124_33+135delTTTTTTTTTTTT		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+118delTTTTTTTTTTTT		intron	N/A	ENSP00000498786.1	P08397-1
	HMBS	ENST00000545621.5	TSL:1	n.33+107_33+118delTTTTTTTTTTTT		intron	N/A	ENSP00000444849.1	F5H4X2
	HMBS	ENST00000545901.5	TSL:1	n.186+107_186+118delTTTTTTTTTTTT		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000973 AC: 65 AN: 66772 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000871

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00146

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00305

Gnomad FIN AF: 0.00178

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000966

Gnomad OTH AF: 0.00117

GnomAD4 exome AF: 0.00491 AC: 3593 AN: 731650 Hom.: 1 AF XY: 0.00494 AC XY: 1789 AN XY: 361880

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0105 AC: 192 AN: 18268

American (AMR) AF: 0.00399 AC: 47 AN: 11794

Ashkenazi Jewish (ASJ) AF: 0.00464 AC: 48 AN: 10350

East Asian (EAS) AF: 0.00409 AC: 32 AN: 7824

South Asian (SAS) AF: 0.00252 AC: 126 AN: 50082

European-Finnish (FIN) AF: 0.00467 AC: 53 AN: 11346

Middle Eastern (MID) AF: 0.00573 AC: 11 AN: 1920

European-Non Finnish (NFE) AF: 0.00495 AC: 2935 AN: 592494

Other (OTH) AF: 0.00540 AC: 149 AN: 27572

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000973 AC: 65 AN: 66808 Hom.: 0 Cov.: 0 AF XY: 0.00108 AC XY: 32 AN XY: 29540

African (AFR) AF: 0.000869 AC: 16 AN: 18402

American (AMR) AF: 0.00146 AC: 7 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: 0.00306 AC: 4 AN: 1308

European-Finnish (FIN) AF: 0.00178 AC: 2 AN: 1126

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

European-Non Finnish (NFE) AF: 0.000966 AC: 35 AN: 36238

Other (OTH) AF: 0.00117 AC: 1 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;