NM_000190.4:c.33+123_33+135dupTTTTTTTTTTTTT

Variant names:

• chr11-119085172-C-CTTTTTTTTTTTTT
• rs549270240
• NM_000190.4:c.33+123_33+135dupTTTTTTTTTTTTT

Variant summary

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

The NM_000190.4(HMBS):​c.33+123_33+135dupTTTTTTTTTTTTT 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 0.0017 (13 hom., cov: 0)
  • Exomes 𝑓: 0.0015 (51 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 = 0.00168 (112/66792) while in subpopulation EAS AF = 0.00641 (9/1404). AF 95% confidence interval is 0.00334. There are 13 homozygotes in GnomAd4. There are 51 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 112 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+123_33+135dupTTTTTTTTTTTTT		intron	N/A	NP_000181.2
	HMBS	NM_001425056.1		c.33+123_33+135dupTTTTTTTTTTTTT		intron	N/A	NP_001411985.1
	HMBS	NM_001425057.1		c.33+123_33+135dupTTTTTTTTTTTTT		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+107insTTTTTTTTTTTTT		intron	N/A	ENSP00000498786.1	P08397-1
	HMBS	ENST00000545621.5	TSL:1	n.33+106_33+107insTTTTTTTTTTTTT		intron	N/A	ENSP00000444849.1	F5H4X2
	HMBS	ENST00000545901.5	TSL:1	n.186+106_186+107insTTTTTTTTTTTTT		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00168 AC: 112 AN: 66756 Hom.: 13 Cov.: 0

Gnomad AFR AF: 0.000871

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00104

Gnomad ASJ AF: 0.00233

Gnomad EAS AF: 0.00642

Gnomad SAS AF: 0.00152

Gnomad FIN AF: 0.000890

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00204

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00152 AC: 1114 AN: 732636 Hom.: 51 Cov.: 0 AF XY: 0.00163 AC XY: 589 AN XY: 362388

African (AFR) AF: 0.000490 AC: 9 AN: 18384

American (AMR) AF: 0.00161 AC: 19 AN: 11818

Ashkenazi Jewish (ASJ) AF: 0.000771 AC: 8 AN: 10370

East Asian (EAS) AF: 0.00281 AC: 22 AN: 7824

South Asian (SAS) AF: 0.00291 AC: 146 AN: 50120

European-Finnish (FIN) AF: 0.00123 AC: 14 AN: 11364

Middle Eastern (MID) AF: 0.000521 AC: 1 AN: 1920

European-Non Finnish (NFE) AF: 0.00143 AC: 846 AN: 593236

Other (OTH) AF: 0.00178 AC: 49 AN: 27600

GnomAD4 genome AF: 0.00168 AC: 112 AN: 66792 Hom.: 13 Cov.: 0 AF XY: 0.00173 AC XY: 51 AN XY: 29536

African (AFR) AF: 0.000870 AC: 16 AN: 18400

American (AMR) AF: 0.00104 AC: 5 AN: 4794

Ashkenazi Jewish (ASJ) AF: 0.00233 AC: 5 AN: 2142

East Asian (EAS) AF: 0.00641 AC: 9 AN: 1404

South Asian (SAS) AF: 0.00153 AC: 2 AN: 1308

European-Finnish (FIN) AF: 0.000890 AC: 1 AN: 1124

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

European-Non Finnish (NFE) AF: 0.00204 AC: 74 AN: 36228

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;