NM_000190.4:c.33+119_33+135dupTTTTTTTTTTTTTTTTT

Variant names:

• chr11-119085172-C-CTTTTTTTTTTTTTTTTT
• rs549270240
• NM_000190.4:c.33+119_33+135dupTTTTTTTTTTTTTTTTT

Variant summary

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

The NM_000190.4(HMBS):​c.33+119_33+135dupTTTTTTTTTTTTTTTTT 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 0.00022 (3 hom., cov: 0)
  • Exomes 𝑓: 0.00011 (6 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: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000225 (15/66804) while in subpopulation EAS AF = 0.00285 (4/1404). AF 95% confidence interval is 0.000973. There are 3 homozygotes in GnomAd4. There are 4 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 15 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+119_33+135dupTTTTTTTTTTTTTTTTT		intron	N/A	NP_000181.2
	HMBS	NM_001425056.1		c.33+119_33+135dupTTTTTTTTTTTTTTTTT		intron	N/A	NP_001411985.1
	HMBS	NM_001425057.1		c.33+119_33+135dupTTTTTTTTTTTTTTTTT		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+107insTTTTTTTTTTTTTTTTT		intron	N/A	ENSP00000498786.1	P08397-1
	HMBS	ENST00000545621.5	TSL:1	n.33+106_33+107insTTTTTTTTTTTTTTTTT		intron	N/A	ENSP00000444849.1	F5H4X2
	HMBS	ENST00000545901.5	TSL:1	n.186+106_186+107insTTTTTTTTTTTTTTTTT		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000225 AC: 15 AN: 66768 Hom.: 3 Cov.: 0

Gnomad AFR AF: 0.000109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00285

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000248

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000115 AC: 84 AN: 732818 Hom.: 6 Cov.: 0 AF XY: 0.000108 AC XY: 39 AN XY: 362474

African (AFR) AF: 0.0000544 AC: 1 AN: 18384

American (AMR) AF: 0.0000846 AC: 1 AN: 11818

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

East Asian (EAS) AF: 0.000511 AC: 4 AN: 7824

South Asian (SAS) AF: 0.000279 AC: 14 AN: 50144

European-Finnish (FIN) AF: 0.000264 AC: 3 AN: 11370

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

European-Non Finnish (NFE) AF: 0.000101 AC: 60 AN: 593378

Other (OTH) AF: 0.0000362 AC: 1 AN: 27608

GnomAD4 genome AF: 0.000225 AC: 15 AN: 66804 Hom.: 3 Cov.: 0 AF XY: 0.000135 AC XY: 4 AN XY: 29540

African (AFR) AF: 0.000109 AC: 2 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: 0.00285 AC: 4 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: 0.000248 AC: 9 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

Other links and lift over

dbSNP: rs549270240; hg19: chr11-118955882;