11-119084969-C-T

Variant names:

• chr11-119084969-C-T
• rs589925
• NM_000190.4:c.-65C>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.-65C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.428 in 1,609,972 control chromosomes in the GnomAD database, including 154,375 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (11592 hom., cov: 32)
  • Exomes 𝑓: 0.44 (142783 hom.)
• Consequence: HMBS NM_000190.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.461
• Publications: 17 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: AD, SD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 11-119084969-C-T is Benign according to our data. Variant chr11-119084969-C-T is described in ClinVar as Benign. ClinVar VariationId is 302723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.725 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.-65C>T		5_prime_UTR	Exon 1 of 14	NP_000181.2
	HMBS	NM_001425056.1		c.-65C>T		5_prime_UTR	Exon 1 of 14	NP_001411985.1
	HMBS	NM_001425057.1		c.-65C>T		5_prime_UTR	Exon 1 of 14	NP_001411986.1	A0A3F2YNY7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMBS	ENST00000652429.1	MANE Select	c.-65C>T		5_prime_UTR	Exon 1 of 14	ENSP00000498786.1	P08397-1
	HMBS	ENST00000545621.5	TSL:1	n.-65C>T		non_coding_transcript_exon	Exon 1 of 10	ENSP00000444849.1	F5H4X2
	HMBS	ENST00000545901.5	TSL:1	n.89C>T		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes AF: 0.361 AC: 54876 AN: 151846 Hom.: 11591 Cov.: 32

Gnomad AFR AF: 0.155

Gnomad AMI AF: 0.329

Gnomad AMR AF: 0.307

Gnomad ASJ AF: 0.423

Gnomad EAS AF: 0.745

Gnomad SAS AF: 0.506

Gnomad FIN AF: 0.534

Gnomad MID AF: 0.385

Gnomad NFE AF: 0.430

Gnomad OTH AF: 0.362

GnomAD4 exome AF: 0.435 AC: 634514 AN: 1458004 Hom.: 142783 Cov.: 32 AF XY: 0.438 AC XY: 317600 AN XY: 725442

African (AFR) AF: 0.141 AC: 4708 AN: 33410

American (AMR) AF: 0.271 AC: 12089 AN: 44598

Ashkenazi Jewish (ASJ) AF: 0.421 AC: 10979 AN: 26080

East Asian (EAS) AF: 0.762 AC: 30239 AN: 39668

South Asian (SAS) AF: 0.488 AC: 42032 AN: 86164

European-Finnish (FIN) AF: 0.524 AC: 27509 AN: 52530

Middle Eastern (MID) AF: 0.404 AC: 2327 AN: 5758

European-Non Finnish (NFE) AF: 0.432 AC: 478846 AN: 1109520

Other (OTH) AF: 0.428 AC: 25785 AN: 60276

GnomAD4 genome AF: 0.361 AC: 54890 AN: 151968 Hom.: 11592 Cov.: 32 AF XY: 0.368 AC XY: 27338 AN XY: 74274

African (AFR) AF: 0.155 AC: 6412 AN: 41484

American (AMR) AF: 0.307 AC: 4698 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.423 AC: 1467 AN: 3472

East Asian (EAS) AF: 0.745 AC: 3821 AN: 5130

South Asian (SAS) AF: 0.507 AC: 2444 AN: 4822

European-Finnish (FIN) AF: 0.534 AC: 5641 AN: 10560

Middle Eastern (MID) AF: 0.390 AC: 114 AN: 292

European-Non Finnish (NFE) AF: 0.430 AC: 29228 AN: 67908

Other (OTH) AF: 0.364 AC: 766 AN: 2104

Alfa AF: 0.394 Hom.: 12577

Bravo AF: 0.334

Asia WGS AF: 0.586 AC: 2039 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Acute intermittent porphyria (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	6.5
DANN	Benign	0.88
PhyloP100		-0.46
PromoterAI		0.058	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=300/0	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: rs589925; hg19: chr11-118955679; COSMIC: COSV53827963; COSMIC: COSV53827963;