11-119089022-C-T

Variant names:

• chr11-119089022-C-T
• rs549893
• NM_000190.4:c.161-60C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000190.4(HMBS):​c.161-60C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.541 in 1,353,884 control chromosomes in the GnomAD database, including 203,291 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (26792 hom., cov: 32)
  • Exomes 𝑓: 0.54 (176499 hom.)
• Consequence: HMBS NM_000190.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.229
• Publications: 14 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 11-119089022-C-T is Benign according to our data. Variant chr11-119089022-C-T is described in ClinVar as Benign. ClinVar VariationId is 1183585.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.706 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000190.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMBS	NM_000190.4	MANE Select	c.161-60C>T		intron	N/A	NP_000181.2
	HMBS	NM_001425056.1		c.161-60C>T		intron	N/A	NP_001411985.1
	HMBS	NM_001425057.1		c.161-78C>T		intron	N/A	NP_001411986.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMBS	ENST00000652429.1	MANE Select	c.161-60C>T		intron	N/A	ENSP00000498786.1
	HMBS	ENST00000392841.1	TSL:1	c.110-60C>T		intron	N/A	ENSP00000376584.1
	HMBS	ENST00000545621.5	TSL:1	n.*56-60C>T		intron	N/A	ENSP00000444849.1

Frequencies

GnomAD3 genomes AF: 0.584 AC: 88650 AN: 151890 Hom.: 26759 Cov.: 32

Gnomad AFR AF: 0.712

Gnomad AMI AF: 0.660

Gnomad AMR AF: 0.663

Gnomad ASJ AF: 0.518

Gnomad EAS AF: 0.246

Gnomad SAS AF: 0.440

Gnomad FIN AF: 0.443

Gnomad MID AF: 0.544

Gnomad NFE AF: 0.548

Gnomad OTH AF: 0.580

GnomAD4 exome AF: 0.535 AC: 643589 AN: 1201876 Hom.: 176499 Cov.: 17 AF XY: 0.532 AC XY: 324948 AN XY: 610958

African (AFR) AF: 0.722 AC: 20411 AN: 28286

American (AMR) AF: 0.708 AC: 31466 AN: 44416

Ashkenazi Jewish (ASJ) AF: 0.522 AC: 12774 AN: 24480

East Asian (EAS) AF: 0.233 AC: 8961 AN: 38502

South Asian (SAS) AF: 0.454 AC: 36807 AN: 81104

European-Finnish (FIN) AF: 0.458 AC: 24272 AN: 53052

Middle Eastern (MID) AF: 0.515 AC: 2575 AN: 5002

European-Non Finnish (NFE) AF: 0.547 AC: 478477 AN: 875242

Other (OTH) AF: 0.538 AC: 27846 AN: 51792

GnomAD4 genome AF: 0.584 AC: 88740 AN: 152008 Hom.: 26792 Cov.: 32 AF XY: 0.577 AC XY: 42852 AN XY: 74280

African (AFR) AF: 0.713 AC: 29546 AN: 41460

American (AMR) AF: 0.663 AC: 10130 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.518 AC: 1799 AN: 3470

East Asian (EAS) AF: 0.247 AC: 1271 AN: 5156

South Asian (SAS) AF: 0.439 AC: 2118 AN: 4826

European-Finnish (FIN) AF: 0.443 AC: 4671 AN: 10542

Middle Eastern (MID) AF: 0.548 AC: 161 AN: 294

European-Non Finnish (NFE) AF: 0.548 AC: 37221 AN: 67948

Other (OTH) AF: 0.579 AC: 1221 AN: 2110

Alfa AF: 0.574 Hom.: 8559

Bravo AF: 0.608

Asia WGS AF: 0.386 AC: 1340 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

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.7
DANN	Benign	0.63
PhyloP100		0.23
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs549893; hg19: chr11-118959732; COSMIC: COSV53828774; COSMIC: COSV53828774;