rs139596860

Variant names:

• chrX-55009187-T-A
• rs139596860
• NM_000032.5:c.1757A>T

Your query was ambiguous. Multiple possible variants found:

• chrX-55009187-T-A
• chrX-55009187-T-G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000032.5(ALAS2):​c.1757A>T​(p.Tyr586Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000399 in 1,205,917 control chromosomes in the GnomAD database, including 1 homozygotes. There are 141 hemizygotes in GnomAD. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., 67 hem., cov: 23)
  • Exomes 𝑓: 0.00024 (1 hom. 74 hem.)
• Consequence: ALAS2 NM_000032.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2 O:1
• Conservation: PhyloP100: 0.262
• Publications: 8 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]

APEX2 (HGNC:17889): (apurinic/apyrimidinic endodeoxyribonuclease 2) Apurinic/apyrimidinic (AP) sites occur frequently in DNA molecules by spontaneous hydrolysis, by DNA damaging agents or by DNA glycosylases that remove specific abnormal bases. AP sites are pre-mutagenic lesions that can prevent normal DNA replication so the cell contains systems to identify and repair such sites. Class II AP endonucleases cleave the phosphodiester backbone 5' to the AP site. This gene encodes a protein shown to have a weak class II AP endonuclease activity. Most of the encoded protein is located in the nucleus but some is also present in mitochondria. This protein may play an important role in both nuclear and mitochondrial base excision repair. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Nov 2012]

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0068839192).
• BP6: Variant X-55009187-T-A is Benign according to our data. Variant chrX-55009187-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 40978.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00195 (217/111123) while in subpopulation AFR AF = 0.00668 (204/30557). AF 95% confidence interval is 0.00593. There are 0 homozygotes in GnomAd4. There are 67 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 67 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000032.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALAS2	NM_000032.5	MANE Select	c.1757A>T	p.Tyr586Phe	missense	Exon 11 of 11	NP_000023.2	P22557-1
	ALAS2	NM_001037968.4		c.1718A>T	p.Tyr573Phe	missense	Exon 11 of 11	NP_001033057.1	P22557-4
	ALAS2	NM_001037967.4		c.1646A>T	p.Tyr549Phe	missense	Exon 10 of 10	NP_001033056.1	P22557-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALAS2	ENST00000650242.1	MANE Select	c.1757A>T	p.Tyr586Phe	missense	Exon 11 of 11	ENSP00000497236.1	P22557-1
	ALAS2	ENST00000396198.7	TSL:5	c.1718A>T	p.Tyr573Phe	missense	Exon 11 of 11	ENSP00000379501.3	P22557-4
	ALAS2	ENST00000335854.8	TSL:2	c.1646A>T	p.Tyr549Phe	missense	Exon 10 of 10	ENSP00000337131.4	P22557-2

Frequencies

GnomAD3 genomes AF: 0.00185 AC: 206 AN: 111072 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00633

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00114

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000672

GnomAD2 exomes AF: 0.000563 AC: 97 AN: 172239 AF XY: 0.000310

Gnomad AFR exome AF: 0.00645

Gnomad AMR exome AF: 0.000564

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000131

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000241 AC: 264 AN: 1094794 Hom.: 1 Cov.: 30 AF XY: 0.000205 AC XY: 74 AN XY: 360564

African (AFR) AF: 0.00671 AC: 177 AN: 26380

American (AMR) AF: 0.000459 AC: 16 AN: 34868

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19309

East Asian (EAS) AF: 0.00 AC: 0 AN: 30139

South Asian (SAS) AF: 0.000113 AC: 6 AN: 53163

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40276

Middle Eastern (MID) AF: 0.00170 AC: 7 AN: 4128

European-Non Finnish (NFE) AF: 0.0000119 AC: 10 AN: 840553

Other (OTH) AF: 0.00104 AC: 48 AN: 45978

GnomAD4 genome AF: 0.00195 AC: 217 AN: 111123 Hom.: 0 Cov.: 23 AF XY: 0.00201 AC XY: 67 AN XY: 33359

African (AFR) AF: 0.00668 AC: 204 AN: 30557

American (AMR) AF: 0.00114 AC: 12 AN: 10496

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2638

East Asian (EAS) AF: 0.00 AC: 0 AN: 3522

South Asian (SAS) AF: 0.00 AC: 0 AN: 2585

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5988

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52936

Other (OTH) AF: 0.000664 AC: 1 AN: 1506

Alfa AF: 0.000435 Hom.: 2

Bravo AF: 0.00210

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00808 AC: 31

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000717 AC: 87

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	1	not provided (4)
-	-	1	Developmental and epileptic encephalopathy, 36 (1)
-	1	-	X-linked sideroblastic anemia 1 (1)
-	-	-	X-linked erythropoietic protoporphyria (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	16
DANN	Benign	0.87
DEOGEN2	Benign	0.28	T
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.0069	T
MetaSVM	Uncertain	-0.093	T
MutationAssessor	Benign	0.46	N
PhyloP100		0.26
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.89	N
REVEL	Benign	0.28
Sift	Benign	0.085	T
Sift4G	Benign	0.20	T
Polyphen		0.016	B
Vest4		0.15
MVP		0.83
MPC		0.45
ClinPred		0.0035	T
GERP RS		4.2
Varity_R		0.17
gMVP		0.67
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs139596860; hg19: chrX-55035620;