3-52204759-C-G

Variant names:

• chr3-52204759-C-G
• rs1699258972
• NM_000688.6:c.644C>G

Variant summary

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

The NM_000688.6(ALAS1):​c.644C>G​(p.Thr215Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,882 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: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ALAS1 NM_000688.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.17

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=0.28761995).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALAS1	NM_000688.6	c.644C>G	p.Thr215Ser	missense_variant	Exon 6 of 12	ENST00000484952.6	NP_000679.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALAS1	ENST00000484952.6	c.644C>G	p.Thr215Ser	missense_variant	Exon 6 of 12	1	NM_000688.6	ENSP00000418779.1
ALAS1	ENST00000310271.6	c.644C>G	p.Thr215Ser	missense_variant	Exon 5 of 11	1		ENSP00000309259.2
ALAS1	ENST00000469224.5	c.644C>G	p.Thr215Ser	missense_variant	Exon 5 of 11	1		ENSP00000417719.1
ALAS1	ENST00000394965.6	c.644C>G	p.Thr215Ser	missense_variant	Exon 6 of 12	2		ENSP00000378416.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461882 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

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.: 32

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.644C>G (p.T215S) alteration is located in exon 6 (coding exon 4) of the ALAS1 gene. This alteration results from a C to G substitution at nucleotide position 644, causing the threonine (T) at amino acid position 215 to be replaced by a serine (S). 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	0.23
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.23	T;T;T;T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.088
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.85	.;.;.;D
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.29	T;T;T;T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Benign	1.9	L;L;L;L
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.36	N;N;N;N
REVEL	Uncertain	0.37
Sift	Benign	0.67	T;T;T;T
Sift4G	Benign	0.81	T;T;T;T
Polyphen		0.012	B;B;B;B
Vest4		0.33
MutPred		0.36		Gain of loop (P = 0.0435);Gain of loop (P = 0.0435);Gain of loop (P = 0.0435);Gain of loop (P = 0.0435);
MVP		0.71
MPC		0.20
ClinPred		0.84	D
GERP RS		4.9
Varity_R		0.11
gMVP		0.71

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: rs1699258972; hg19: chr3-52238775;