rs1006195

Variant names:

• chr11-119088159-G-T
• rs1006195
• NM_000190.4:c.34-96G>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 27 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 -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 VariationId 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 rank	MANE	Protein	UniProt
HMBS	NM_000190.4	c.34-96G>T		intron_variant	Intron 1 of 13	ENST00000652429.1	NP_000181.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMBS	ENST00000652429.1	c.34-96G>T		intron_variant	Intron 1 of 13		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

African (AFR) AF: 0.223 AC: 7350 AN: 32904

American (AMR) AF: 0.242 AC: 10780 AN: 44628

Ashkenazi Jewish (ASJ) AF: 0.394 AC: 10220 AN: 25928

East Asian (EAS) AF: 0.144 AC: 5704 AN: 39480

South Asian (SAS) AF: 0.371 AC: 31631 AN: 85284

European-Finnish (FIN) AF: 0.290 AC: 15420 AN: 53180

Middle Eastern (MID) AF: 0.374 AC: 2045 AN: 5466

European-Non Finnish (NFE) AF: 0.404 AC: 438945 AN: 1085748

Other (OTH) AF: 0.368 AC: 21845 AN: 59330

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

African (AFR) AF: 0.231 AC: 9590 AN: 41496

American (AMR) AF: 0.288 AC: 4409 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.386 AC: 1341 AN: 3470

East Asian (EAS) AF: 0.165 AC: 857 AN: 5186

South Asian (SAS) AF: 0.360 AC: 1741 AN: 4830

European-Finnish (FIN) AF: 0.283 AC: 3005 AN: 10608

Middle Eastern (MID) AF: 0.398 AC: 117 AN: 294

European-Non Finnish (NFE) AF: 0.400 AC: 27204 AN: 68002

Other (OTH) AF: 0.363 AC: 767 AN: 2114

Alfa AF: 0.359 Hom.: 4564

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	14
DANN	Benign	0.75
PhyloP100		-0.10
PromoterAI		0.047	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1006195; hg19: chr11-118958869; COSMIC: COSV107225327; COSMIC: COSV107225327;