chr3-131014155-T-C

Variant names:

• chr3-131014155-T-C
• rs1302019976
• NM_014065.4:c.1942A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014065.4(ASTE1):​c.1942A>G​(p.Thr648Ala) 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. 16/21 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: ASTE1 NM_014065.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.29
• Publications: 0 publications found

Genes affected

ASTE1 (HGNC:25021): (asteroid homolog 1) Predicted to enable nuclease activity. Predicted to be involved in nucleic acid phosphodiester bond hydrolysis. [provided by Alliance of Genome Resources, Apr 2022]

ATP2C1 (HGNC:13211): (ATPase secretory pathway Ca2+ transporting 1) The protein encoded by this gene belongs to the family of P-type cation transport ATPases. This magnesium-dependent enzyme catalyzes the hydrolysis of ATP coupled with the transport of calcium ions. Defects in this gene cause Hailey-Hailey disease, an autosomal dominant disorder. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Aug 2011]

ATP2C1 Gene-Disease associations (from GenCC):

• Hailey-Hailey disease

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.049753845).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014065.4. 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
	ASTE1	NM_014065.4	MANE Select	c.1942A>G	p.Thr648Ala	missense	Exon 6 of 6	NP_054784.2
	ASTE1	NM_001288950.2		c.2017A>G	p.Thr673Ala	missense	Exon 7 of 7	NP_001275879.1	D6RG30
	ATP2C1	NM_001378511.1		c.2857-1997T>C		intron	N/A	NP_001365440.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASTE1	ENST00000264992.8	TSL:1 MANE Select	c.1942A>G	p.Thr648Ala	missense	Exon 6 of 6	ENSP00000264992.3	Q2TB18-1
	ASTE1	ENST00000514044.5	TSL:1	c.2017A>G	p.Thr673Ala	missense	Exon 7 of 7	ENSP00000426421.1	D6RG30
	ATP2C1	ENST00000359644.7	TSL:1	c.2755-1997T>C		intron	N/A	ENSP00000352665.3	P98194-9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

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	0.061
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.19
DANN	Benign	0.32
DEOGEN2	Benign	0.0098	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.050	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		-1.3
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.38	N
REVEL	Benign	0.0080
Sift	Benign	0.51	T
Sift4G	Benign	0.57	T
Polyphen		0.0060	B
Vest4		0.14
MutPred		0.41		Gain of glycosylation at T672 (P = 0.0199)
MVP		0.15
MPC		0.14
ClinPred		0.059	T
GERP RS		-8.7
Varity_R		0.026
gMVP		0.19
Mutation Taster		=98/2	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: rs1302019976; hg19: chr3-130732999;