3-52204006-C-A

Variant names:

• chr3-52204006-C-A
• rs1699244210
• NM_000688.6:c.571C>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000688.6(ALAS1):​c.571C>A​(p.Pro191Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000689 in 1,450,932 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ALAS1 NM_000688.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.68

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41642123).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALAS1	NM_000688.6	c.571C>A	p.Pro191Thr	missense_variant	Exon 5 of 12	ENST00000484952.6	NP_000679.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALAS1	ENST00000484952.6	c.571C>A	p.Pro191Thr	missense_variant	Exon 5 of 12	1	NM_000688.6	ENSP00000418779.1
ALAS1	ENST00000310271.6	c.571C>A	p.Pro191Thr	missense_variant	Exon 4 of 11	1		ENSP00000309259.2
ALAS1	ENST00000469224.5	c.571C>A	p.Pro191Thr	missense_variant	Exon 4 of 11	1		ENSP00000417719.1
ALAS1	ENST00000394965.6	c.571C>A	p.Pro191Thr	missense_variant	Exon 5 of 12	2		ENSP00000378416.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1450932 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 721142

Gnomad4 AFR exome AF: 0.0000302

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 18, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.571C>A (p.P191T) alteration is located in exon 5 (coding exon 3) of the ALAS1 gene. This alteration results from a C to A substitution at nucleotide position 571, causing the proline (P) at amino acid position 191 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.25	T;T;T;T
Eigen	Benign	0.068
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.88	.;.;.;D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.42	T;T;T;T
MetaSVM	Uncertain	0.50	D
MutationAssessor	Benign	1.8	L;L;L;L
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.79	N;N;N;N
REVEL	Uncertain	0.49
Sift	Benign	0.29	T;T;T;T
Sift4G	Benign	0.35	T;T;T;T
Polyphen		0.048	B;B;B;B
Vest4		0.55
MutPred		0.38		Loss of helix (P = 0.0093);Loss of helix (P = 0.0093);Loss of helix (P = 0.0093);Loss of helix (P = 0.0093);
MVP		0.85
MPC		0.40
ClinPred		0.63	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24
gMVP		0.68

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: rs1699244210; hg19: chr3-52238022;