11-119085006-A-C

Position:

• chr11-119085006-A-C

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 302724.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Likely_benign=1, Uncertain_significance=1}.
• 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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HMBS	NM_000190.4	c.-28A>C		5_prime_UTR_variant	1/14	ENST00000652429.1	NP_000181.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HMBS	ENST00000652429.1	c.-28A>C		5_prime_UTR_variant	1/14		NM_000190.4	ENSP00000498786	P3

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

GnomAD3 exomes AF: 0.00421 AC: 1057 AN: 250862 Hom.: 8 AF XY: 0.00421 AC XY: 572 AN XY: 135814

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 SAS exome AF: 0.00444

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

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.0126

Gnomad4 ASJ exome AF: 0.00784

Gnomad4 EAS exome AF: 0.00113

Gnomad4 SAS exome AF: 0.00449

Gnomad4 FIN exome AF: 0.00117

Gnomad4 NFE exome AF: 0.00294

Gnomad4 OTH exome AF: 0.00283

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

Gnomad4 AFR AF: 0.000506

Gnomad4 AMR AF: 0.0132

Gnomad4 ASJ AF: 0.00749

Gnomad4 EAS AF: 0.00155

Gnomad4 SAS AF: 0.00477

Gnomad4 FIN AF: 0.000849

Gnomad4 NFE AF: 0.00393

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00434 Hom.: 0

Bravo AF: 0.00388

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 22, 2022	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	HMBS: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 16, 2021	- -

Acute intermittent porphyria Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.1
DANN	Benign	0.43

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

Publications

LitVar

Other links and lift over

dbSNP: rs201349602; hg19: chr11-118955716;