Variant 3-52202663-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000688.6(ALAS1):c.356G>A(p.Gly119Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ALAS1
NM_000688.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.89

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 made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1616686).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALAS1	NM_000688.6 linkuse as main transcript	c.356G>A	p.Gly119Asp	missense_variant	4/12	ENST00000484952.6	NP_000679.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALAS1	ENST00000484952.6 linkuse as main transcript	c.356G>A	p.Gly119Asp	missense_variant	4/12	1	NM_000688.6	ENSP00000418779	P1	P13196-1
ALAS1	ENST00000310271.6 linkuse as main transcript	c.356G>A	p.Gly119Asp	missense_variant	3/11	1		ENSP00000309259	P1	P13196-1
ALAS1	ENST00000469224.5 linkuse as main transcript	c.356G>A	p.Gly119Asp	missense_variant	3/11	1		ENSP00000417719	P1	P13196-1
ALAS1	ENST00000394965.6 linkuse as main transcript	c.356G>A	p.Gly119Asp	missense_variant	4/12	2		ENSP00000378416	P1	P13196-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250912

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135630

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 13, 2021

The c.356G>A (p.G119D) alteration is located in exon 4 (coding exon 2) of the ALAS1 gene. This alteration results from a G to A substitution at nucleotide position 356, causing the glycine (G) at amino acid position 119 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Uncertain

0.096

BayesDel_noAF

Benign

-0.10

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.21

T;T;T;T

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.026

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.80

.;.;.;T

M_CAP

Benign

0.061

MetaRNN

Benign

0.16

T;T;T;T

MetaSVM

Uncertain

-0.14

MutationAssessor

Benign

1.0

L;L;L;L

MutationTaster

Benign

0.94

N;N;N;N

PrimateAI

Benign

0.36

PROVEAN

Benign

0.060

N;N;N;N

REVEL

Uncertain

0.30

Sift

Benign

0.54

T;T;T;T

Sift4G

Benign

0.54

T;T;T;T

Polyphen

0.0

B;B;B;B

Vest4

0.27

MutPred

0.43

Loss of helix (P = 0.0033);Loss of helix (P = 0.0033);Loss of helix (P = 0.0033);Loss of helix (P = 0.0033);

MVP

0.42

MPC

0.28

ClinPred

0.36

GERP RS

4.3

Varity_R

0.039

gMVP

0.12

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over