11-119088570-T-C

Variant names:

• chr11-119088570-T-C
• rs1144041
• NM_000190.4:c.88-65T>C

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.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
• Publications: 5 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=-0.78).
• BP6: Variant 11-119088570-T-C is Benign according to our data. Variant chr11-119088570-T-C is described in ClinVar as Benign. ClinVar VariationId 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMBS	NM_000190.4	MANE Select	c.88-65T>C		intron	N/A	NP_000181.2
	HMBS	NM_001425056.1		c.88-65T>C		intron	N/A	NP_001411985.1
	HMBS	NM_001425057.1		c.88-65T>C		intron	N/A	NP_001411986.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMBS	ENST00000652429.1	MANE Select	c.88-65T>C		intron	N/A	ENSP00000498786.1
	HMBS	ENST00000392841.1	TSL:1	c.37-65T>C		intron	N/A	ENSP00000376584.1
	HMBS	ENST00000545621.5	TSL:1	n.88-65T>C		intron	N/A	ENSP00000444849.1

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

African (AFR) AF: 0.335 AC: 9238 AN: 27596

American (AMR) AF: 0.0229 AC: 1012 AN: 44288

Ashkenazi Jewish (ASJ) AF: 0.00242 AC: 59 AN: 24414

East Asian (EAS) AF: 0.00 AC: 0 AN: 38474

South Asian (SAS) AF: 0.000805 AC: 65 AN: 80772

European-Finnish (FIN) AF: 0.000638 AC: 34 AN: 53318

Middle Eastern (MID) AF: 0.0309 AC: 157 AN: 5080

European-Non Finnish (NFE) AF: 0.00212 AC: 1805 AN: 850218

Other (OTH) AF: 0.0265 AC: 1343 AN: 50732

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

African (AFR) AF: 0.315 AC: 13081 AN: 41472

American (AMR) AF: 0.0464 AC: 710 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4824

European-Finnish (FIN) AF: 0.000754 AC: 8 AN: 10616

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.00288 AC: 196 AN: 68014

Other (OTH) AF: 0.0686 AC: 145 AN: 2114

Alfa AF: 0.101 Hom.: 306

Bravo AF: 0.108

Asia WGS AF: 0.0300 AC: 103 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	13
DANN	Benign	0.72
PhyloP100		0.13
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1144041; hg19: chr11-118959280;