11-119085006-A-C

Variant names:

• chr11-119085006-A-C
• rs201349602
• NM_000190.4:c.-28A>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000190.4(HMBS):​c.-28A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00328 in 1,613,618 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0037 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0032 (26 hom.)
• Consequence: HMBS NM_000190.4 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -0.820
• Publications: 2 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: Genomics England PanelApp, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 11-119085006-A-C is Benign according to our data. Variant chr11-119085006-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 302724.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00373 (568/152192) while in subpopulation AMR AF = 0.0132 (202/15292). AF 95% confidence interval is 0.0117. There are 2 homozygotes in GnomAd4. There are 291 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 568 SD,AD gene.

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.-28A>C		5_prime_UTR	Exon 1 of 14	NP_000181.2
	HMBS	NM_001425056.1		c.-28A>C		5_prime_UTR	Exon 1 of 14	NP_001411985.1
	HMBS	NM_001425057.1		c.-28A>C		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.-28A>C		5_prime_UTR	Exon 1 of 14	ENSP00000498786.1	P08397-1
	HMBS	ENST00000545621.5	TSL:1	n.-28A>C		non_coding_transcript_exon	Exon 1 of 10	ENSP00000444849.1	F5H4X2
	HMBS	ENST00000545901.5	TSL:1	n.126A>C		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes AF: 0.00372 AC: 566 AN: 152074 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0132

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.00136

Gnomad SAS AF: 0.00456

Gnomad FIN AF: 0.000849

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00393

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00421 AC: 1057 AN: 250862 AF XY: 0.00421

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.0114

Gnomad ASJ exome AF: 0.00815

Gnomad EAS exome AF: 0.000980

Gnomad FIN exome AF: 0.00111

Gnomad NFE exome AF: 0.00332

Gnomad OTH exome AF: 0.00392

GnomAD4 exome AF: 0.00323 AC: 4718 AN: 1461426 Hom.: 26 Cov.: 43 AF XY: 0.00337 AC XY: 2448 AN XY: 727018

African (AFR) AF: 0.000269 AC: 9 AN: 33480

American (AMR) AF: 0.0126 AC: 563 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00784 AC: 205 AN: 26134

East Asian (EAS) AF: 0.00113 AC: 45 AN: 39698

South Asian (SAS) AF: 0.00449 AC: 387 AN: 86252

European-Finnish (FIN) AF: 0.00117 AC: 62 AN: 52998

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5768

European-Non Finnish (NFE) AF: 0.00294 AC: 3267 AN: 1111982

Other (OTH) AF: 0.00283 AC: 171 AN: 60392

GnomAD4 genome AF: 0.00373 AC: 568 AN: 152192 Hom.: 2 Cov.: 31 AF XY: 0.00391 AC XY: 291 AN XY: 74412

African (AFR) AF: 0.000506 AC: 21 AN: 41534

American (AMR) AF: 0.0132 AC: 202 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00749 AC: 26 AN: 3472

East Asian (EAS) AF: 0.00155 AC: 8 AN: 5152

South Asian (SAS) AF: 0.00477 AC: 23 AN: 4820

European-Finnish (FIN) AF: 0.000849 AC: 9 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00393 AC: 267 AN: 67998

Other (OTH) AF: 0.00568 AC: 12 AN: 2114

Alfa AF: 0.00296 Hom.: 0

Bravo AF: 0.00388

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	2	Acute intermittent porphyria (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.1
DANN	Benign	0.43
PhyloP100		-0.82
PromoterAI		-0.010	Neutral
Mutation Taster		=300/0	polymorphism

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: rs201349602; hg19: chr11-118955716;