X-55009226-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 2P and 17B. PM1 BP4 BP6_Very_Strong BS1 BS2

The NM_000032.5(ALAS2):c.1718C>T(p.Ser573Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000536 in 1,206,177 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 198 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00044 (0 hom., 9 hem., cov: 23)
  • Exomes 𝑓: 0.00055 (0 hom. 189 hem.)
• Consequence: ALAS2 NM_000032.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 4.96

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 Benign. Variant got -15 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_000032.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.27077731).
• BP6: Variant X-55009226-G-A is Benign according to our data. Variant chrX-55009226-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 214091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-55009226-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000441 (49/111173) while in subpopulation NFE AF= 0.000831 (44/52969). AF 95% confidence interval is 0.000635. There are 0 homozygotes in gnomad4. There are 9 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 9 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALAS2	NM_000032.5	c.1718C>T	p.Ser573Phe	missense_variant	11/11	ENST00000650242.1
ALAS2	NM_001037968.4	c.1679C>T	p.Ser560Phe	missense_variant	11/11
ALAS2	NM_001037967.4	c.1607C>T	p.Ser536Phe	missense_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALAS2	ENST00000650242.1	c.1718C>T	p.Ser573Phe	missense_variant	11/11		NM_000032.5	P1
ALAS2	ENST00000396198.7	c.1679C>T	p.Ser560Phe	missense_variant	11/11	5
ALAS2	ENST00000335854.8	c.1607C>T	p.Ser536Phe	missense_variant	10/10	2
ALAS2	ENST00000498636.1	c.*16C>T		3_prime_UTR_variant	5/5	3

Frequencies

GnomAD3 genomes AF: 0.000441 AC: 49 AN: 111121 Hom.: 0 Cov.: 23 AF XY: 0.000270 AC XY: 9 AN XY: 33289

Gnomad AFR AF: 0.000131

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000384

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000831

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000272 AC: 47 AN: 172744 Hom.: 0 AF XY: 0.000308 AC XY: 18 AN XY: 58530

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: 0.0000574

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000602

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000545 AC: 597 AN: 1095004 Hom.: 0 Cov.: 31 AF XY: 0.000524 AC XY: 189 AN XY: 360668

Gnomad4 AFR exome AF: 0.0000758

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000751

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000685

Gnomad4 OTH exome AF: 0.000326

GnomAD4 genome AF: 0.000441 AC: 49 AN: 111173 Hom.: 0 Cov.: 23 AF XY: 0.000270 AC XY: 9 AN XY: 33351

Gnomad4 AFR AF: 0.000131

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000386

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000831

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000654 Hom.: 22

Bravo AF: 0.000400

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000743 AC: 5

ExAC AF: 0.000231 AC: 28

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Oct 23, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 30, 2021	This variant is associated with the following publications: (PMID: 30678654) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	ALAS2: BS2 -

ALAS2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 24, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

X-linked sideroblastic anemia 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	0.0033	T
BayesDel_noAF	Uncertain	0.13
Cadd	Uncertain	25
Dann	Uncertain	1.0
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.95	D;.;D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Benign	0.27	T;T;T;T
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.8	D;.;D;D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0010	D;.;D;D
Sift4G	Uncertain	0.0020	D;.;D;D
Polyphen		0.95	.;P;P;.
Vest4		0.42
MVP		0.94
MPC		0.60
ClinPred		0.22	T
GERP RS		5.4
Varity_R		0.83
gMVP		0.78

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: rs201799139; hg19: chrX-55035659;