3-52202617-A-C

Variant names:

• chr3-52202617-A-C
• rs1339399260
• NM_000688.6:c.310A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000688.6(ALAS1):​c.310A>C​(p.Thr104Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ALAS1 NM_000688.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0210
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.094751865).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000688.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALAS1	NM_000688.6	MANE Select	c.310A>C	p.Thr104Pro	missense	Exon 4 of 12	NP_000679.1	P13196-1
	ALAS1	NM_001304444.1		c.361A>C	p.Thr121Pro	missense	Exon 4 of 12	NP_001291373.1	B4DVA0
	ALAS1	NM_001304443.1		c.310A>C	p.Thr104Pro	missense	Exon 3 of 11	NP_001291372.1	P13196-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALAS1	ENST00000484952.6	TSL:1 MANE Select	c.310A>C	p.Thr104Pro	missense	Exon 4 of 12	ENSP00000418779.1	P13196-1
	ALAS1	ENST00000310271.6	TSL:1	c.310A>C	p.Thr104Pro	missense	Exon 3 of 11	ENSP00000309259.2	P13196-1
	ALAS1	ENST00000469224.5	TSL:1	c.310A>C	p.Thr104Pro	missense	Exon 3 of 11	ENSP00000417719.1	P13196-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Uncertain	0.084	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.095	T
MetaSVM	Uncertain	0.034	D
MutationAssessor	Benign	1.8	L
PhyloP100		0.021
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.60	N
REVEL	Uncertain	0.30
Sift	Uncertain	0.024	D
Sift4G	Benign	0.23	T
Polyphen		0.0	B
Vest4		0.17
MutPred		0.26		Loss of loop (P = 0.0374)
MVP		0.51
MPC		0.28
ClinPred		0.033	T
GERP RS		1.3
Varity_R		0.10
gMVP		0.20
Mutation Taster		=83/17	polymorphism

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

Other links and lift over

dbSNP: rs1339399260; hg19: chr3-52236633;