3-52202615-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000688.6(ALAS1):c.308G>A(p.Gly103Asp) variant causes a missense 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ALAS1 NM_000688.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.55

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]

ACMG classification

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=0.14899272).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALAS1	NM_000688.6	c.308G>A	p.Gly103Asp	missense_variant	4/12	ENST00000484952.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALAS1	ENST00000484952.6	c.308G>A	p.Gly103Asp	missense_variant	4/12	1	NM_000688.6	P1
ALAS1	ENST00000310271.6	c.308G>A	p.Gly103Asp	missense_variant	3/11	1		P1
ALAS1	ENST00000469224.5	c.308G>A	p.Gly103Asp	missense_variant	3/11	1		P1
ALAS1	ENST00000394965.6	c.308G>A	p.Gly103Asp	missense_variant	4/12	2		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 27, 2021

The c.308G>A (p.G103D) 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 308, causing the glycine (G) at amino acid position 103 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	0.10
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.22	T;T;T;T
Eigen	Benign	-0.20
Eigen_PC	Benign	0.015
FATHMM_MKL	Uncertain	0.87	D
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.15	T;T;T;T
MetaSVM	Uncertain	0.10	D
MutationAssessor	Benign	1.7	L;L;L;L
MutationTaster	Benign	0.77	N;N;N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.16	N;N;N;N
REVEL	Benign	0.24
Sift	Benign	0.12	T;T;T;T
Sift4G	Benign	0.66	T;T;T;T
Polyphen		0.0030	B;B;B;B
Vest4		0.26
MutPred		0.22		Loss of loop (P = 0.0128);Loss of loop (P = 0.0128);Loss of loop (P = 0.0128);Loss of loop (P = 0.0128);
MVP		0.62
MPC		0.38
ClinPred		0.52	D
GERP RS		5.2
Varity_R		0.086
gMVP		0.26

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

Other links and lift over

dbSNP: rs1699211112; hg19: chr3-52236631;