3-52199279-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000688.6(ALAS1):c.38G>A(p.Arg13Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0057 in 1,614,072 control chromosomes in the GnomAD database, including 77 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0038 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0059 (72 hom.)
• Consequence: ALAS1 NM_000688.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 6.53

Genes affected

ALAS1 (HGNC:396): (5'-aminolevulinate synthase 1) This gene encodes the mitochondrial enzyme which is catalyzes the rate-limiting step in heme (iron-protoporphyrin) biosynthesis. The enzyme encoded by this gene is the housekeeping enzyme; a separate gene encodes a form of the enzyme that is specific for erythroid tissue. The level of the mature encoded protein is regulated by heme: high levels of heme down-regulate the mature enzyme in mitochondria while low heme levels up-regulate. A pseudogene of this gene is located on chromosome 12. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jan 2015]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009139299).
• BP6: Variant 3-52199279-G-A is Benign according to our data. Variant chr3-52199279-G-A is described in ClinVar as [Benign]. Clinvar id is 776349.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0038 (578/152184) while in subpopulation SAS AF= 0.0264 (127/4816). AF 95% confidence interval is 0.0226. There are 5 homozygotes in gnomad4. There are 298 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALAS1	NM_000688.6	c.38G>A	p.Arg13Gln	missense_variant	3/12	ENST00000484952.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALAS1	ENST00000484952.6	c.38G>A	p.Arg13Gln	missense_variant	3/12	1	NM_000688.6	P1
ALAS1	ENST00000310271.6	c.38G>A	p.Arg13Gln	missense_variant	2/11	1		P1
ALAS1	ENST00000469224.5	c.38G>A	p.Arg13Gln	missense_variant	2/11	1		P1
ALAS1	ENST00000394965.6	c.38G>A	p.Arg13Gln	missense_variant	3/12	2		P1

Frequencies

GnomAD3 genomes AF: 0.00380 AC: 578 AN: 152066 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.000894

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.0263

Gnomad FIN AF: 0.00142

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00479

Gnomad OTH AF: 0.00288

GnomAD3 exomes AF: 0.00579 AC: 1457 AN: 251490 Hom.: 12 AF XY: 0.00691 AC XY: 939 AN XY: 135920

Gnomad AFR exome AF: 0.000861

Gnomad AMR exome AF: 0.00243

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.00239

Gnomad SAS exome AF: 0.0252

Gnomad FIN exome AF: 0.00157

Gnomad NFE exome AF: 0.00417

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00590 AC: 8628 AN: 1461888 Hom.: 72 Cov.: 31 AF XY: 0.00650 AC XY: 4729 AN XY: 727242

Gnomad4 AFR exome AF: 0.000657

Gnomad4 AMR exome AF: 0.00230

Gnomad4 ASJ exome AF: 0.00161

Gnomad4 EAS exome AF: 0.00224

Gnomad4 SAS exome AF: 0.0252

Gnomad4 FIN exome AF: 0.00155

Gnomad4 NFE exome AF: 0.00516

Gnomad4 OTH exome AF: 0.00581

GnomAD4 genome AF: 0.00380 AC: 578 AN: 152184 Hom.: 5 Cov.: 33 AF XY: 0.00401 AC XY: 298 AN XY: 74400

Gnomad4 AFR AF: 0.000891

Gnomad4 AMR AF: 0.00307

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00232

Gnomad4 SAS AF: 0.0264

Gnomad4 FIN AF: 0.00142

Gnomad4 NFE AF: 0.00478

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00399 Hom.: 6

Bravo AF: 0.00287

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00395 AC: 34

ExAC AF: 0.00617 AC: 749

Asia WGS AF: 0.00866 AC: 30 AN: 3478

EpiCase AF: 0.00414

EpiControl AF: 0.00504

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 05, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.069	T
BayesDel_noAF	Pathogenic	0.15
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.43	T;T;T;T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	1.0	D
MetaRNN	Benign	0.0091	T;T;T;T
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Uncertain	2.3	M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.9	N;N;N;N
REVEL	Pathogenic	0.78
Sift	Benign	0.074	T;T;T;T
Sift4G	Uncertain	0.048	D;D;D;D
Polyphen		0.90	P;P;P;P
Vest4		0.59
MVP		0.85
MPC		0.74
ClinPred		0.034	T
GERP RS		5.0
Varity_R		0.19
gMVP		0.52

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: rs35338461; hg19: chr3-52233295;