Genetic Variant ALAS1:p.Pro45Ser (chr3-52199374-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000688.6(ALAS1):c.133C>T(p.Pro45Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P45T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

ALAS1
NM_000688.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0910

Publications

0 publications found

Variant links:

Genes affected

ALAS1 (HGNC:396): (5'-aminolevulinate synthase 1) This gene encodes the mitochondrial enzyme which is catalyzes the rate-limiting step in heme (iron-protoporphyrin) biosynthesis. The enzyme encoded by this gene is the housekeeping enzyme; a separate gene encodes a form of the enzyme that is specific for erythroid tissue. The level of the mature encoded protein is regulated by heme: high levels of heme down-regulate the mature enzyme in mitochondria while low heme levels up-regulate. A pseudogene of this gene is located on chromosome 12. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jan 2015]

ALAS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11155918).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000688.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ALAS1	NM_000688.6	MANE Select	c.133C>T	p.Pro45Ser	missense	Exon 3 of 12	NP_000679.1	P13196-1
ALAS1	NM_001304444.1		c.184C>T	p.Pro62Ser	missense	Exon 3 of 12	NP_001291373.1	B4DVA0
ALAS1	NM_001304443.1		c.133C>T	p.Pro45Ser	missense	Exon 2 of 11	NP_001291372.1	P13196-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ALAS1	ENST00000484952.6	TSL:1 MANE Select	c.133C>T	p.Pro45Ser	missense	Exon 3 of 12	ENSP00000418779.1	P13196-1
ALAS1	ENST00000310271.6	TSL:1	c.133C>T	p.Pro45Ser	missense	Exon 2 of 11	ENSP00000309259.2	P13196-1
ALAS1	ENST00000469224.5	TSL:1	c.133C>T	p.Pro45Ser	missense	Exon 2 of 11	ENSP00000417719.1	P13196-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1112012

Other (OTH)

AF:

0.0000166

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.025

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.21

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.28

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.76

M_CAP

Benign

0.047

MetaRNN

Benign

0.11

MetaSVM

Benign

-0.30

MutationAssessor

Benign

-0.51

PhyloP100

0.091

PrimateAI

Benign

0.35

PROVEAN

Benign

0.64

REVEL

Benign

0.15

Sift

Benign

0.83

Sift4G

Benign

0.79

Polyphen

0.0

Vest4

0.12

MutPred

0.28

Loss of helix (P = 0.0167)

MVP

0.40

MPC

0.22

ClinPred

0.28

GERP RS

3.2

Varity_R

0.044

gMVP

0.20

Mutation Taster

=76/24

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