rs139596860

chrX-55009187-T-AchrX-55009187-T-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting 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. 13/20 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:3 B:1 O:1
• 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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0068839192).
• 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 male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Hemizygotes in GnomAd at 57 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALAS2	NM_000032.5	c.1757A>T	p.Tyr586Phe	missense_variant	11/11	ENST00000650242.1
ALAS2	NM_001037968.4	c.1718A>T	p.Tyr573Phe	missense_variant	11/11
ALAS2	NM_001037967.4	c.1646A>T	p.Tyr549Phe	missense_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALAS2	ENST00000650242.1	c.1757A>T	p.Tyr586Phe	missense_variant	11/11		NM_000032.5	P1
ALAS2	ENST00000396198.7	c.1718A>T	p.Tyr573Phe	missense_variant	11/11	5
ALAS2	ENST00000335854.8	c.1646A>T	p.Tyr549Phe	missense_variant	10/10	2
ALAS2	ENST00000498636.1	c.*55A>T		3_prime_UTR_variant	5/5	3

Frequencies

GnomAD3 genomes AF: 0.00185 AC: 206 AN: 111072 Hom.: 0 Cov.: 23 AF XY: 0.00171 AC XY: 57 AN XY: 33298

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

GnomAD3 exomes AF: 0.000563 AC: 97 AN: 172239 Hom.: 0 AF XY: 0.000310 AC XY: 18 AN XY: 58151

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 SAS exome AF: 0.0000577

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

Gnomad4 AFR exome AF: 0.00671

Gnomad4 AMR exome AF: 0.000459

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000113

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000119

Gnomad4 OTH exome AF: 0.00104

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

Gnomad4 AFR AF: 0.00668

Gnomad4 AMR AF: 0.00114

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000664

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 05, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 30, 2016	The Y586F variant has previously been reported as heterozygous in a single female patient with moderate congenital erythropoietic porphyria (To-Figueras et al., 2011). Functional analysis of Y586F found that it is assocaited with only a mild gain of function in vitro (To-Figueras et al., 2011). However, the NHLBI Exome Sequencing Project reports Y586F was observed in 31/3835 alleles from individuals of African-American background, indicating it may be a rare, benign variant in this population. The Y586F variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. In silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

X-linked sideroblastic anemia 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

X-linked erythropoietic protoporphyria Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

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
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.81	T;.;T;T
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.0069	T;T;T;T
MetaSVM	Uncertain	-0.093	T
MutationTaster	Benign	0.90	N;N;N
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.89	N;.;N;N
REVEL	Benign	0.28
Sift	Benign	0.085	T;.;T;T
Sift4G	Benign	0.20	T;.;T;T
Polyphen		0.016	.;B;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

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;