chr11-119088570-T-C

Position:

• chr11-119088570-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000190.4(HMBS):​c.88-65T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.021 in 1,327,078 control chromosomes in the GnomAD database, including 3,792 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.093 (2125 hom., cov: 33)
  • Exomes 𝑓: 0.012 (1667 hom.)
• Consequence: HMBS NM_000190.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.128

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 11-119088570-T-C is Benign according to our data. Variant chr11-119088570-T-C is described in ClinVar as [Benign]. Clinvar id is 1246134.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.311 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HMBS	NM_000190.4	c.88-65T>C		intron_variant		ENST00000652429.1	NP_000181.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HMBS	ENST00000652429.1	c.88-65T>C		intron_variant			NM_000190.4	ENSP00000498786.1

Frequencies

GnomAD3 genomes AF: 0.0927 AC: 14099 AN: 152068 Hom.: 2105 Cov.: 33

Gnomad AFR AF: 0.315

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0465

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00288

Gnomad OTH AF: 0.0693

GnomAD4 exome AF: 0.0117 AC: 13713 AN: 1174892 Hom.: 1667 AF XY: 0.0102 AC XY: 6111 AN XY: 598352

Gnomad4 AFR exome AF: 0.335

Gnomad4 AMR exome AF: 0.0229

Gnomad4 ASJ exome AF: 0.00242

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000805

Gnomad4 FIN exome AF: 0.000638

Gnomad4 NFE exome AF: 0.00212

Gnomad4 OTH exome AF: 0.0265

GnomAD4 genome AF: 0.0930 AC: 14160 AN: 152186 Hom.: 2125 Cov.: 33 AF XY: 0.0903 AC XY: 6720 AN XY: 74432

Gnomad4 AFR AF: 0.315

Gnomad4 AMR AF: 0.0464

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.000754

Gnomad4 NFE AF: 0.00288

Gnomad4 OTH AF: 0.0686

Alfa AF: 0.101 Hom.: 306

Bravo AF: 0.108

Asia WGS AF: 0.0300 AC: 103 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 21, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	13
DANN	Benign	0.72
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1144041; hg19: chr11-118959280;