11-119085172-CTTTTTTTTTTTTTTTTTTTTTT-CTTTTTTTTT

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_000190.4(HMBS):​c.33+123_33+135delTTTTTTTTTTTTT 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 DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.089 (264 hom., cov: 0)
  • Exomes 𝑓: 0.095 (273 hom.)
  • Failed GnomAD Quality Control
• Consequence: HMBS NM_000190.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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: SD, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 11-119085172-CTTTTTTTTTTTTT-C is Benign according to our data. Variant chr11-119085172-CTTTTTTTTTTTTT-C is described in ClinVar as Likely_benign. ClinVar VariationId is 445546.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.126 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMBS	NM_000190.4	c.33+123_33+135delTTTTTTTTTTTTT		intron_variant	Intron 1 of 13	ENST00000652429.1	NP_000181.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMBS	ENST00000652429.1	c.33+107_33+119delTTTTTTTTTTTTT		intron_variant	Intron 1 of 13		NM_000190.4	ENSP00000498786.1

Frequencies

GnomAD3 genomes AF: 0.0893 AC: 5983 AN: 66970 Hom.: 265 Cov.: 0

Gnomad AFR AF: 0.0265

Gnomad AMI AF: 0.0891

Gnomad AMR AF: 0.0752

Gnomad ASJ AF: 0.131

Gnomad EAS AF: 0.000712

Gnomad SAS AF: 0.142

Gnomad FIN AF: 0.292

Gnomad MID AF: 0.113

Gnomad NFE AF: 0.115

Gnomad OTH AF: 0.119

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0947 AC: 69113 AN: 730024 Hom.: 273 AF XY: 0.0939 AC XY: 33907 AN XY: 360978

African (AFR) AF: 0.0186 AC: 340 AN: 18302

American (AMR) AF: 0.0384 AC: 452 AN: 11772

Ashkenazi Jewish (ASJ) AF: 0.129 AC: 1331 AN: 10282

East Asian (EAS) AF: 0.00179 AC: 14 AN: 7816

South Asian (SAS) AF: 0.0651 AC: 3243 AN: 49790

European-Finnish (FIN) AF: 0.132 AC: 1495 AN: 11298

Middle Eastern (MID) AF: 0.0831 AC: 159 AN: 1914

European-Non Finnish (NFE) AF: 0.101 AC: 59552 AN: 591352

Other (OTH) AF: 0.0919 AC: 2527 AN: 27498

GnomAD4 genome AF: 0.0892 AC: 5979 AN: 67004 Hom.: 264 Cov.: 0 AF XY: 0.0917 AC XY: 2719 AN XY: 29652

African (AFR) AF: 0.0265 AC: 488 AN: 18414

American (AMR) AF: 0.0751 AC: 362 AN: 4818

Ashkenazi Jewish (ASJ) AF: 0.131 AC: 282 AN: 2148

East Asian (EAS) AF: 0.000711 AC: 1 AN: 1406

South Asian (SAS) AF: 0.143 AC: 189 AN: 1326

European-Finnish (FIN) AF: 0.292 AC: 339 AN: 1160

Middle Eastern (MID) AF: 0.0811 AC: 6 AN: 74

European-Non Finnish (NFE) AF: 0.115 AC: 4170 AN: 36340

Other (OTH) AF: 0.118 AC: 101 AN: 858

Alfa AF: 0.0246 Hom.: 67

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

May 15, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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;