rs28935484

Variant names:

• chrX-55021121-T-A
• rs28935484
• NM_000032.5:c.569A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000032.5(ALAS2):​c.569A>T​(p.Asp190Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D190H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: ALAS2 NM_000032.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.02
• Publications: 7 publications found

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]

ALAS2 Gene-Disease associations (from GenCC):

• X-linked erythropoietic protoporphyria

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• X-linked sideroblastic anemia 1

  Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.943
• PP5: Variant X-55021121-T-A is Pathogenic according to our data. Variant chrX-55021121-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 10474.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALAS2	NM_000032.5	c.569A>T	p.Asp190Val	missense_variant	Exon 5 of 11	ENST00000650242.1	NP_000023.2
ALAS2	NM_001037968.4	c.530A>T	p.Asp177Val	missense_variant	Exon 5 of 11		NP_001033057.1
ALAS2	NM_001037967.4	c.458A>T	p.Asp153Val	missense_variant	Exon 4 of 10		NP_001033056.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALAS2	ENST00000650242.1	c.569A>T	p.Asp190Val	missense_variant	Exon 5 of 11		NM_000032.5	ENSP00000497236.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

X-linked sideroblastic anemia 1 Pathogenic:1

Jul 15, 1997

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.57
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.74	.;D;D;.;.;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;.;D;D;D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.1	.;M;M;.;.;.
PhyloP100		8.0
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-3.7	D;.;D;D;.;.
REVEL	Pathogenic	0.86
Sift	Benign	0.030	D;.;T;D;.;.
Sift4G	Uncertain	0.055	T;.;T;T;.;.
Polyphen		0.036	.;B;B;.;.;.
Vest4		0.64
MutPred		0.81		.;Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);.;.;.;
MVP		0.99
MPC		0.96
ClinPred		0.99	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.90
Mutation Taster		=7/93	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.25		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs28935484; hg19: chrX-55047554;