X-55009187-T-G

Variant summary

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

The NM_000032.5(ALAS2):c.1757A>C(p.Tyr586Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000009 in 111,073 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts 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. Y586F) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000090 (0 hom., 1 hem., cov: 23)
• Consequence: ALAS2 NM_000032.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.262

Genes affected

ALAS2 (HGNC:397): (5'-aminolevulinate synthase 2) The product of this gene specifies an erythroid-specific mitochondrially located enzyme. The encoded protein catalyzes the first step in the heme biosynthetic pathway. Defects in this gene cause X-linked pyridoxine-responsive sideroblastic anemia. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

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=0.11588526).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALAS2	NM_000032.5	c.1757A>C	p.Tyr586Ser	missense_variant	11/11	ENST00000650242.1
ALAS2	NM_001037968.4	c.1718A>C	p.Tyr573Ser	missense_variant	11/11
ALAS2	NM_001037967.4	c.1646A>C	p.Tyr549Ser	missense_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALAS2	ENST00000650242.1	c.1757A>C	p.Tyr586Ser	missense_variant	11/11		NM_000032.5	P1
ALAS2	ENST00000396198.7	c.1718A>C	p.Tyr573Ser	missense_variant	11/11	5
ALAS2	ENST00000335854.8	c.1646A>C	p.Tyr549Ser	missense_variant	10/10	2
ALAS2	ENST00000498636.1	c.*55A>C		3_prime_UTR_variant	5/5	3

Frequencies

GnomAD3 genomes AF: 0.00000900 AC: 1 AN: 111073 Hom.: 0 Cov.: 23 AF XY: 0.0000300 AC XY: 1 AN XY: 33299

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000385

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000900 AC: 1 AN: 111073 Hom.: 0 Cov.: 23 AF XY: 0.0000300 AC XY: 1 AN XY: 33299

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000385

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
Cadd	Benign	17
Dann	Benign	0.86
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.82	T;.;T;T
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.12	T;T;T;T
MetaSVM	Uncertain	0.27	D
MutationTaster	Benign	0.59	D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.51	N;.;N;N
REVEL	Uncertain	0.34
Sift	Benign	0.10	T;.;T;T
Sift4G	Benign	0.25	T;.;T;T
Polyphen		0.065	.;B;B;.
Vest4		0.21
MutPred		0.25		.;Gain of relative solvent accessibility (P = 0.005);Gain of relative solvent accessibility (P = 0.005);.;
MVP		0.78
MPC		0.71
ClinPred		0.052	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.88

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: rs139596860; hg19: chrX-55035620;