rs1006195

Positions:

• chr11-119088159-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000190.4(HMBS):​c.34-96G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.375 in 1,584,156 control chromosomes in the GnomAD database, including 115,117 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (8542 hom., cov: 33)
  • Exomes 𝑓: 0.38 (106575 hom.)
• Consequence: HMBS NM_000190.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.104

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 -16 ACMG points.

• BP6: Variant 11-119088159-G-T is Benign according to our data. Variant chr11-119088159-G-T is described in ClinVar as [Benign]. Clinvar id is 1246575.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.396 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HMBS	NM_000190.4	c.34-96G>T		intron_variant		ENST00000652429.1	NP_000181.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HMBS	ENST00000652429.1	c.34-96G>T		intron_variant			NM_000190.4	ENSP00000498786.1

Frequencies

GnomAD3 genomes AF: 0.325 AC: 49416 AN: 152090 Hom.: 8547 Cov.: 33

Gnomad AFR AF: 0.231

Gnomad AMI AF: 0.423

Gnomad AMR AF: 0.289

Gnomad ASJ AF: 0.386

Gnomad EAS AF: 0.165

Gnomad SAS AF: 0.361

Gnomad FIN AF: 0.283

Gnomad MID AF: 0.405

Gnomad NFE AF: 0.400

Gnomad OTH AF: 0.361

GnomAD4 exome AF: 0.380 AC: 543940 AN: 1431948 Hom.: 106575 Cov.: 24 AF XY: 0.381 AC XY: 272062 AN XY: 714036

Gnomad4 AFR exome AF: 0.223

Gnomad4 AMR exome AF: 0.242

Gnomad4 ASJ exome AF: 0.394

Gnomad4 EAS exome AF: 0.144

Gnomad4 SAS exome AF: 0.371

Gnomad4 FIN exome AF: 0.290

Gnomad4 NFE exome AF: 0.404

Gnomad4 OTH exome AF: 0.368

GnomAD4 genome AF: 0.325 AC: 49417 AN: 152208 Hom.: 8542 Cov.: 33 AF XY: 0.319 AC XY: 23734 AN XY: 74430

Gnomad4 AFR AF: 0.231

Gnomad4 AMR AF: 0.288

Gnomad4 ASJ AF: 0.386

Gnomad4 EAS AF: 0.165

Gnomad4 SAS AF: 0.360

Gnomad4 FIN AF: 0.283

Gnomad4 NFE AF: 0.400

Gnomad4 OTH AF: 0.363

Alfa AF: 0.356 Hom.: 3739

Bravo AF: 0.319

Asia WGS AF: 0.271 AC: 940 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 19, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	14
DANN	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.26		Position offset: 20

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

Publications

LitVar

Other links and lift over

dbSNP: rs1006195; hg19: chr11-118958869;