11-119090521-T-C

Variant names:

• chr11-119090521-T-C
• rs494048
• NM_000190.4:c.498+256T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000652429.1(HMBS):​c.498+256T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.591 in 152,022 control chromosomes in the GnomAD database, including 27,695 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.59 (27695 hom., cov: 31)
• Consequence: HMBS ENST00000652429.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.17
• Publications: 15 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 11-119090521-T-C is Benign according to our data. Variant chr11-119090521-T-C is described in ClinVar as Benign. ClinVar VariationId is 1286339.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.746 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000652429.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMBS	NM_000190.4	MANE Select	c.498+256T>C		intron	N/A	NP_000181.2
	HMBS	NM_001425056.1		c.498+256T>C		intron	N/A	NP_001411985.1
	HMBS	NM_001425057.1		c.480+256T>C		intron	N/A	NP_001411986.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMBS	ENST00000652429.1	MANE Select	c.498+256T>C		intron	N/A	ENSP00000498786.1
	HMBS	ENST00000392841.1	TSL:1	c.447+256T>C		intron	N/A	ENSP00000376584.1
	HMBS	ENST00000545621.5	TSL:1	n.*393+256T>C		intron	N/A	ENSP00000444849.1

Frequencies

GnomAD3 genomes AF: 0.591 AC: 89734 AN: 151902 Hom.: 27658 Cov.: 31

Gnomad AFR AF: 0.753

Gnomad AMI AF: 0.593

Gnomad AMR AF: 0.665

Gnomad ASJ AF: 0.520

Gnomad EAS AF: 0.258

Gnomad SAS AF: 0.476

Gnomad FIN AF: 0.438

Gnomad MID AF: 0.544

Gnomad NFE AF: 0.537

Gnomad OTH AF: 0.585

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.591 AC: 89831 AN: 152022 Hom.: 27695 Cov.: 31 AF XY: 0.585 AC XY: 43426 AN XY: 74294

African (AFR) AF: 0.753 AC: 31219 AN: 41464

American (AMR) AF: 0.665 AC: 10167 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.520 AC: 1806 AN: 3472

East Asian (EAS) AF: 0.258 AC: 1334 AN: 5172

South Asian (SAS) AF: 0.474 AC: 2280 AN: 4806

European-Finnish (FIN) AF: 0.438 AC: 4613 AN: 10542

Middle Eastern (MID) AF: 0.551 AC: 162 AN: 294

European-Non Finnish (NFE) AF: 0.537 AC: 36483 AN: 67962

Other (OTH) AF: 0.583 AC: 1227 AN: 2104

Alfa AF: 0.562 Hom.: 12756

Bravo AF: 0.615

Asia WGS AF: 0.413 AC: 1432 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.40
DANN	Benign	0.82
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs494048; hg19: chr11-118961231;