11-119090521-T-C

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000190.4(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 NM_000190.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.17

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMBS	NM_000190.4	c.498+256T>C		intron_variant	Intron 8 of 13	ENST00000652429.1	NP_000181.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMBS	ENST00000652429.1	c.498+256T>C		intron_variant	Intron 8 of 13		NM_000190.4	ENSP00000498786.1

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

Gnomad4 AFR AF: 0.753

Gnomad4 AMR AF: 0.665

Gnomad4 ASJ AF: 0.520

Gnomad4 EAS AF: 0.258

Gnomad4 SAS AF: 0.474

Gnomad4 FIN AF: 0.438

Gnomad4 NFE AF: 0.537

Gnomad4 OTH AF: 0.583

Alfa AF: 0.581 Hom.: 8354

Bravo AF: 0.615

Asia WGS AF: 0.413 AC: 1432 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.40
DANN	Benign	0.82

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

Publications

LitVar

Other links and lift over

dbSNP: rs494048; hg19: chr11-118961231;