11-119084969-C-T

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.-65C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.428 in 1,609,972 control chromosomes in the GnomAD database, including 154,375 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.36 (11592 hom., cov: 32)
  • Exomes 𝑓: 0.44 (142783 hom.)
• Consequence: HMBS NM_000190.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.461

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=-0.72).
• BP6: Variant 11-119084969-C-T is Benign according to our data. Variant chr11-119084969-C-T is described in ClinVar as [Benign]. Clinvar id is 302723.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.725 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HMBS	NM_000190.4	c.-65C>T		5_prime_UTR_variant	1/14	ENST00000652429.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HMBS	ENST00000652429.1	c.-65C>T		5_prime_UTR_variant	1/14		NM_000190.4	P3

Frequencies

GnomAD3 genomes AF: 0.361 AC: 54876 AN: 151846 Hom.: 11591 Cov.: 32

Gnomad AFR AF: 0.155

Gnomad AMI AF: 0.329

Gnomad AMR AF: 0.307

Gnomad ASJ AF: 0.423

Gnomad EAS AF: 0.745

Gnomad SAS AF: 0.506

Gnomad FIN AF: 0.534

Gnomad MID AF: 0.385

Gnomad NFE AF: 0.430

Gnomad OTH AF: 0.362

GnomAD4 exome AF: 0.435 AC: 634514 AN: 1458004 Hom.: 142783 Cov.: 32 AF XY: 0.438 AC XY: 317600 AN XY: 725442

Gnomad4 AFR exome AF: 0.141

Gnomad4 AMR exome AF: 0.271

Gnomad4 ASJ exome AF: 0.421

Gnomad4 EAS exome AF: 0.762

Gnomad4 SAS exome AF: 0.488

Gnomad4 FIN exome AF: 0.524

Gnomad4 NFE exome AF: 0.432

Gnomad4 OTH exome AF: 0.428

GnomAD4 genome AF: 0.361 AC: 54890 AN: 151968 Hom.: 11592 Cov.: 32 AF XY: 0.368 AC XY: 27338 AN XY: 74274

Gnomad4 AFR AF: 0.155

Gnomad4 AMR AF: 0.307

Gnomad4 ASJ AF: 0.423

Gnomad4 EAS AF: 0.745

Gnomad4 SAS AF: 0.507

Gnomad4 FIN AF: 0.534

Gnomad4 NFE AF: 0.430

Gnomad4 OTH AF: 0.364

Alfa AF: 0.409 Hom.: 9656

Bravo AF: 0.334

Asia WGS AF: 0.586 AC: 2039 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Acute intermittent porphyria Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
Cadd	Benign	6.5
Dann	Benign	0.88
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs589925; hg19: chr11-118955679; COSMIC: COSV53827963; COSMIC: COSV53827963;