NM_000190.4:c.29C>T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_000190.4(HMBS):c.29C>T(p.Thr10Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 1,460,504 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T10T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.000011 ( 1 hom. )

Consequence

HMBS
NM_000190.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.870

Publications

2 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 -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.17223907).

BS2

High AC in GnomAdExome4 at 16 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HMBS	NM_000190.4	MANE Select	c.29C>T	p.Thr10Met	missense	Exon 1 of 14	NP_000181.2
HMBS	NM_001425052.1		c.-114C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 14	NP_001411981.1	P08397-2
HMBS	NM_001425053.1		c.-90C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 14	NP_001411982.1	P08397-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HMBS	ENST00000652429.1	MANE Select	c.29C>T	p.Thr10Met	missense	Exon 1 of 14	ENSP00000498786.1	P08397-1
HMBS	ENST00000545621.5	TSL:1	n.29C>T		non_coding_transcript_exon	Exon 1 of 10	ENSP00000444849.1	F5H4X2
HMBS	ENST00000545901.5	TSL:1	n.182C>T		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000120

AC:

AN:

249914

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000110

AC:

AN:

1460504

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

726560

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26114

East Asian (EAS)

AF:

0.000126

AC:

AN:

39598

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52692

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111568

Other (OTH)

AF:

0.000182

AC:

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.000102

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000247

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.012

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.32

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.41

M_CAP

Pathogenic

0.68

MetaRNN

Benign

0.17

MetaSVM

Pathogenic

1.3

MutationAssessor

Benign

1.5

PhyloP100

0.87

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.31

REVEL

Uncertain

0.35

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.033

Polyphen

0.17

Vest4

0.28

MutPred

0.23

Loss of phosphorylation at T10 (P = 0.0284)

MVP

0.49

MPC

0.38

ClinPred

0.64

GERP RS

5.0

PromoterAI

0.22

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.077

Mutation Taster

=94/6

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over