Genetic Variant NM_000190.4:c.499C>A (chr11-119091413-C-A) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP7

The NM_000190.4(HMBS):c.499C>A(p.Arg167Arg) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HMBS
NM_000190.4 splice_region, synonymous

Scores

Splicing: ADA: 0.002313

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.50

Publications

27 publications found

Variant links:

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)

HMBS links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.25).

BP7

Synonymous conserved (PhyloP=2.5 with no splicing effect.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HMBS	NM_000190.4	MANE Select	c.499C>A	p.Arg167Arg	splice_region synonymous	Exon 9 of 14	NP_000181.2
HMBS	NM_001425056.1		c.499C>A	p.Arg167Arg	splice_region synonymous	Exon 9 of 14	NP_001411985.1
HMBS	NM_001425057.1		c.481C>A	p.Arg161Arg	splice_region synonymous	Exon 9 of 14	NP_001411986.1	A0A3F2YNY7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HMBS	ENST00000652429.1	MANE Select	c.499C>A	p.Arg167Arg	splice_region synonymous	Exon 9 of 14	ENSP00000498786.1	P08397-1
HMBS	ENST00000392841.1	TSL:1	c.448C>A	p.Arg150Arg	splice_region synonymous	Exon 9 of 14	ENSP00000376584.1	P08397-2
HMBS	ENST00000545621.5	TSL:1	n.*394C>A		splice_region non_coding_transcript_exon	Exon 9 of 10	ENSP00000444849.1	F5H4X2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1398000

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

689650

African (AFR)

AF:

0.00

AC:

AN:

31572

American (AMR)

AF:

0.00

AC:

AN:

35700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25178

East Asian (EAS)

AF:

0.00

AC:

AN:

35730

South Asian (SAS)

AF:

0.00

AC:

AN:

79216

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49256

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1077708

Other (OTH)

AF:

0.00

AC:

AN:

57944

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Benign

0.90

PhyloP100

2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0023

dbscSNV1_RF

Benign

0.15

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over