X-55009219-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_000032.5(ALAS2):c.1725C>T(p.Phe575=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000058 in 1,206,025 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 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 0.000018 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0000046 (0 hom. 2 hem.)
• Consequence: ALAS2 NM_000032.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.311

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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant X-55009219-G-A is Benign according to our data. Variant chrX-55009219-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 753250.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.311 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALAS2	NM_000032.5	c.1725C>T	p.Phe575=	synonymous_variant	11/11	ENST00000650242.1
ALAS2	NM_001037968.4	c.1686C>T	p.Phe562=	synonymous_variant	11/11
ALAS2	NM_001037967.4	c.1614C>T	p.Phe538=	synonymous_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALAS2	ENST00000650242.1	c.1725C>T	p.Phe575=	synonymous_variant	11/11		NM_000032.5	P1
ALAS2	ENST00000396198.7	c.1686C>T	p.Phe562=	synonymous_variant	11/11	5
ALAS2	ENST00000335854.8	c.1614C>T	p.Phe538=	synonymous_variant	10/10	2
ALAS2	ENST00000498636.1	c.*23C>T		3_prime_UTR_variant	5/5	3

Frequencies

GnomAD3 genomes AF: 0.0000180 AC: 2 AN: 111039 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33215

Gnomad AFR AF: 0.0000656

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

GnomAD4 exome AF: 0.00000457 AC: 5 AN: 1094986 Hom.: 0 Cov.: 31 AF XY: 0.00000555 AC XY: 2 AN XY: 360646

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.0000287

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: 0.00000357

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000180 AC: 2 AN: 111039 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33215

Gnomad4 AFR AF: 0.0000656

Gnomad4 AMR AF: 0.00

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

Bravo AF: 0.00000756

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Mar 10, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
Cadd	Benign	2.2
Dann	Benign	0.80

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: rs1189487849; hg19: chrX-55035652;