X-55009297-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000032.5(ALAS2):c.1647T>C(p.Asp549=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000173 in 1,202,928 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 66 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 0.00091 (0 hom., 25 hem., cov: 22)
  • Exomes 𝑓: 0.000098 (0 hom. 41 hem.)
• Consequence: ALAS2 NM_000032.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0100

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant X-55009297-A-G is Benign according to our data. Variant chrX-55009297-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 388258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.01 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000909 (101/111072) while in subpopulation AFR AF= 0.00311 (95/30533). AF 95% confidence interval is 0.00261. There are 0 homozygotes in gnomad4. There are 25 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 25 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALAS2	NM_000032.5	c.1647T>C	p.Asp549=	synonymous_variant	11/11	ENST00000650242.1
ALAS2	NM_001037968.4	c.1608T>C	p.Asp536=	synonymous_variant	11/11
ALAS2	NM_001037967.4	c.1536T>C	p.Asp512=	synonymous_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALAS2	ENST00000650242.1	c.1647T>C	p.Asp549=	synonymous_variant	11/11		NM_000032.5	P1
ALAS2	ENST00000498636.1	c.776T>C	p.Met259Thr	missense_variant	5/5	3
ALAS2	ENST00000396198.7	c.1608T>C	p.Asp536=	synonymous_variant	11/11	5
ALAS2	ENST00000335854.8	c.1536T>C	p.Asp512=	synonymous_variant	10/10	2

Frequencies

GnomAD3 genomes AF: 0.000910 AC: 101 AN: 111018 Hom.: 0 Cov.: 22 AF XY: 0.000753 AC XY: 25 AN XY: 33210

Gnomad AFR AF: 0.00312

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000477

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00417

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000219 AC: 36 AN: 164582 Hom.: 0 AF XY: 0.000186 AC XY: 10 AN XY: 53656

Gnomad AFR exome AF: 0.00257

Gnomad AMR exome AF: 0.000230

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000980 AC: 107 AN: 1091856 Hom.: 0 Cov.: 31 AF XY: 0.000114 AC XY: 41 AN XY: 358170

Gnomad4 AFR exome AF: 0.00326

Gnomad4 AMR exome AF: 0.000290

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000238

Gnomad4 OTH exome AF: 0.000196

GnomAD4 genome AF: 0.000909 AC: 101 AN: 111072 Hom.: 0 Cov.: 22 AF XY: 0.000751 AC XY: 25 AN XY: 33274

Gnomad4 AFR AF: 0.00311

Gnomad4 AMR AF: 0.000477

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: 0.00

Alfa AF: 0.000498 Hom.: 1

Bravo AF: 0.000929

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 17, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 30, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	6.2
Dann	Benign	0.59
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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: rs35075981; hg19: chrX-55035730;