NM_000190.4:c.33+122_33+135dupTTTTTTTTTTTTTT

Variant names:

• chr11-119085172-C-CTTTTTTTTTTTTTT
• rs549270240
• NM_000190.4:c.33+122_33+135dupTTTTTTTTTTTTTT

Variant summary

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

The NM_000190.4(HMBS):​c.33+122_33+135dupTTTTTTTTTTTTTT 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 0.00075 (9 hom., cov: 0)
  • Exomes 𝑓: 0.00084 (29 hom.)
• 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 = 0.000748 (50/66804) while in subpopulation EAS AF = 0.00427 (6/1404). AF 95% confidence interval is 0.00186. There are 9 homozygotes in GnomAd4. There are 25 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 50 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+122_33+135dupTTTTTTTTTTTTTT		intron	N/A	NP_000181.2
	HMBS	NM_001425056.1		c.33+122_33+135dupTTTTTTTTTTTTTT		intron	N/A	NP_001411985.1
	HMBS	NM_001425057.1		c.33+122_33+135dupTTTTTTTTTTTTTT		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+107insTTTTTTTTTTTTTT		intron	N/A	ENSP00000498786.1	P08397-1
	HMBS	ENST00000545621.5	TSL:1	n.33+106_33+107insTTTTTTTTTTTTTT		intron	N/A	ENSP00000444849.1	F5H4X2
	HMBS	ENST00000545901.5	TSL:1	n.186+106_186+107insTTTTTTTTTTTTTT		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000749 AC: 50 AN: 66768 Hom.: 9 Cov.: 0

Gnomad AFR AF: 0.000109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00140

Gnomad EAS AF: 0.00428

Gnomad SAS AF: 0.00305

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000938

Gnomad OTH AF: 0.00117

GnomAD4 exome AF: 0.000845 AC: 619 AN: 732704 Hom.: 29 Cov.: 0 AF XY: 0.000891 AC XY: 323 AN XY: 362418

African (AFR) AF: 0.00 AC: 0 AN: 18380

American (AMR) AF: 0.000677 AC: 8 AN: 11818

Ashkenazi Jewish (ASJ) AF: 0.000675 AC: 7 AN: 10370

East Asian (EAS) AF: 0.00217 AC: 17 AN: 7820

South Asian (SAS) AF: 0.00168 AC: 84 AN: 50120

European-Finnish (FIN) AF: 0.00167 AC: 19 AN: 11366

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

European-Non Finnish (NFE) AF: 0.000782 AC: 464 AN: 593302

Other (OTH) AF: 0.000724 AC: 20 AN: 27608

GnomAD4 genome AF: 0.000748 AC: 50 AN: 66804 Hom.: 9 Cov.: 0 AF XY: 0.000846 AC XY: 25 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: 0.00140 AC: 3 AN: 2142

East Asian (EAS) AF: 0.00427 AC: 6 AN: 1404

South Asian (SAS) AF: 0.00306 AC: 4 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: 0.000938 AC: 34 AN: 36234

Other (OTH) AF: 0.00117 AC: 1 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;