rs686624

Variant names:

• chr11-119084799-T-A
• rs686624
• NM_000190.4:c.-235T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000190.4(HMBS):​c.-235T>A variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.834 in 612,592 control chromosomes in the GnomAD database, including 214,187 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.83 (52913 hom., cov: 33)
  • Exomes 𝑓: 0.83 (161274 hom.)
• Consequence: HMBS NM_000190.4 upstream_gene
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.630
• Publications: 12 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 11-119084799-T-A is Benign according to our data. Variant chr11-119084799-T-A is described in ClinVar as Benign. ClinVar VariationId is 255484.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.907 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMBS	NM_000190.4	c.-235T>A		upstream_gene_variant		ENST00000652429.1	NP_000181.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMBS	ENST00000652429.1	c.-235T>A		upstream_gene_variant			NM_000190.4	ENSP00000498786.1

Frequencies

GnomAD3 genomes AF: 0.831 AC: 126450 AN: 152112 Hom.: 52879 Cov.: 33

Gnomad AFR AF: 0.864

Gnomad AMI AF: 0.755

Gnomad AMR AF: 0.690

Gnomad ASJ AF: 0.829

Gnomad EAS AF: 0.929

Gnomad SAS AF: 0.879

Gnomad FIN AF: 0.819

Gnomad MID AF: 0.839

Gnomad NFE AF: 0.835

Gnomad OTH AF: 0.837

GnomAD4 exome AF: 0.835 AC: 384304 AN: 460362 Hom.: 161274 AF XY: 0.837 AC XY: 204931 AN XY: 244712

African (AFR) AF: 0.864 AC: 11098 AN: 12846

American (AMR) AF: 0.613 AC: 12940 AN: 21094

Ashkenazi Jewish (ASJ) AF: 0.837 AC: 11781 AN: 14080

East Asian (EAS) AF: 0.926 AC: 28813 AN: 31112

South Asian (SAS) AF: 0.869 AC: 41744 AN: 48024

European-Finnish (FIN) AF: 0.815 AC: 23964 AN: 29406

Middle Eastern (MID) AF: 0.812 AC: 1665 AN: 2050

European-Non Finnish (NFE) AF: 0.837 AC: 230333 AN: 275286

Other (OTH) AF: 0.830 AC: 21966 AN: 26464

GnomAD4 genome AF: 0.831 AC: 126535 AN: 152230 Hom.: 52913 Cov.: 33 AF XY: 0.829 AC XY: 61708 AN XY: 74428

African (AFR) AF: 0.863 AC: 35866 AN: 41536

American (AMR) AF: 0.689 AC: 10531 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.829 AC: 2876 AN: 3470

East Asian (EAS) AF: 0.929 AC: 4816 AN: 5186

South Asian (SAS) AF: 0.879 AC: 4244 AN: 4830

European-Finnish (FIN) AF: 0.819 AC: 8686 AN: 10606

Middle Eastern (MID) AF: 0.837 AC: 246 AN: 294

European-Non Finnish (NFE) AF: 0.835 AC: 56810 AN: 68000

Other (OTH) AF: 0.839 AC: 1773 AN: 2112

Alfa AF: 0.827 Hom.: 6508

Bravo AF: 0.819

Asia WGS AF: 0.900 AC: 3129 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.6
DANN	Benign	0.42
PhyloP100		-0.63
PromoterAI		0.16	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs686624; hg19: chr11-118955509;