11-119091520-G-T

Variant names:

• chr11-119091520-G-T
• rs1131488
• NM_000190.4:c.606G>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000190.4(HMBS):​c.606G>T​(p.Val202Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.266 in 1,546,376 control chromosomes in the GnomAD database, including 56,567 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (4502 hom., cov: 32)
  • Exomes 𝑓: 0.27 (52065 hom.)
• Consequence: HMBS NM_000190.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.11
• Publications: 18 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 11-119091520-G-T is Benign according to our data. Variant chr11-119091520-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255485.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.11 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.279 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.606G>T	p.Val202Val	synonymous	Exon 9 of 14	NP_000181.2
	HMBS	NM_001425056.1		c.606G>T	p.Val202Val	synonymous	Exon 9 of 14	NP_001411985.1
	HMBS	NM_001425057.1		c.588G>T	p.Val196Val	synonymous	Exon 9 of 14	NP_001411986.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMBS	ENST00000652429.1	MANE Select	c.606G>T	p.Val202Val	synonymous	Exon 9 of 14	ENSP00000498786.1
	HMBS	ENST00000392841.1	TSL:1	c.555G>T	p.Val185Val	synonymous	Exon 9 of 14	ENSP00000376584.1
	HMBS	ENST00000545621.5	TSL:1	n.*501G>T		non_coding_transcript_exon	Exon 9 of 10	ENSP00000444849.1

Frequencies

GnomAD3 genomes AF: 0.235 AC: 35815 AN: 152088 Hom.: 4499 Cov.: 32

Gnomad AFR AF: 0.166

Gnomad AMI AF: 0.313

Gnomad AMR AF: 0.201

Gnomad ASJ AF: 0.342

Gnomad EAS AF: 0.171

Gnomad SAS AF: 0.192

Gnomad FIN AF: 0.262

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.282

Gnomad OTH AF: 0.247

GnomAD2 exomes AF: 0.235 AC: 36676 AN: 155800 AF XY: 0.238

Gnomad AFR exome AF: 0.165

Gnomad AMR exome AF: 0.155

Gnomad ASJ exome AF: 0.348

Gnomad EAS exome AF: 0.166

Gnomad FIN exome AF: 0.260

Gnomad NFE exome AF: 0.281

Gnomad OTH exome AF: 0.260

GnomAD4 exome AF: 0.269 AC: 375557 AN: 1394170 Hom.: 52065 Cov.: 29 AF XY: 0.268 AC XY: 184678 AN XY: 688072

African (AFR) AF: 0.163 AC: 5135 AN: 31484

American (AMR) AF: 0.160 AC: 5720 AN: 35700

Ashkenazi Jewish (ASJ) AF: 0.349 AC: 8782 AN: 25142

East Asian (EAS) AF: 0.159 AC: 5664 AN: 35688

South Asian (SAS) AF: 0.200 AC: 15807 AN: 79150

European-Finnish (FIN) AF: 0.251 AC: 12332 AN: 49136

Middle Eastern (MID) AF: 0.276 AC: 1571 AN: 5686

European-Non Finnish (NFE) AF: 0.284 AC: 305246 AN: 1074374

Other (OTH) AF: 0.265 AC: 15300 AN: 57810

GnomAD4 genome AF: 0.235 AC: 35821 AN: 152206 Hom.: 4502 Cov.: 32 AF XY: 0.234 AC XY: 17419 AN XY: 74416

African (AFR) AF: 0.166 AC: 6888 AN: 41548

American (AMR) AF: 0.201 AC: 3072 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.342 AC: 1187 AN: 3468

East Asian (EAS) AF: 0.170 AC: 882 AN: 5178

South Asian (SAS) AF: 0.192 AC: 928 AN: 4822

European-Finnish (FIN) AF: 0.262 AC: 2778 AN: 10596

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.282 AC: 19204 AN: 67988

Other (OTH) AF: 0.250 AC: 528 AN: 2108

Alfa AF: 0.258 Hom.: 10000

Bravo AF: 0.228

Asia WGS AF: 0.187 AC: 654 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	7.1
DANN	Benign	0.81
PhyloP100		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	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: rs1131488; hg19: chr11-118962230; COSMIC: COSV53827924; COSMIC: COSV53827924;