chr4-42485550-A-G

Variant names:

• chr4-42485550-A-G
• rs757790458
• NM_006095.2:c.2270T>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_006095.2(ATP8A1):​c.2270T>C​(p.Val757Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000616 in 1,461,438 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: 0.0000062 (0 hom.)
• Consequence: ATP8A1 NM_006095.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.90
• Publications: 1 publications found

Genes affected

ATP8A1 (HGNC:13531): (ATPase phospholipid transporting 8A1) The P-type adenosinetriphosphatases (P-type ATPases) are a family of proteins which use the free energy of ATP hydrolysis to drive uphill transport of ions across membranes. Several subfamilies of P-type ATPases have been identified. One subfamily catalyzes transport of heavy metal ions. Another subfamily transports non-heavy metal ions (NMHI). The protein encoded by this gene is a member of the third subfamily of P-type ATPases and acts to transport amphipaths, such as phosphatidylserine. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.41017753).
• BS2: High AC in GnomAdExome4 at 9 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006095.2. 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
	ATP8A1	NM_006095.2	MANE Select	c.2270T>C	p.Val757Ala	missense	Exon 25 of 37	NP_006086.1	Q9Y2Q0-1
	ATP8A1	NM_001400024.1		c.2270T>C	p.Val757Ala	missense	Exon 25 of 37	NP_001386953.1
	ATP8A1	NM_001400025.1		c.2246T>C	p.Val749Ala	missense	Exon 25 of 37	NP_001386954.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP8A1	ENST00000381668.9	TSL:1 MANE Select	c.2270T>C	p.Val757Ala	missense	Exon 25 of 37	ENSP00000371084.5	Q9Y2Q0-1
	ATP8A1	ENST00000264449.14	TSL:1	c.2225T>C	p.Val742Ala	missense	Exon 24 of 36	ENSP00000264449.10	Q9Y2Q0-3
	ATP8A1	ENST00000514372.5	TSL:1	n.204+17900T>C		intron	N/A	ENSP00000426495.1	H0YAA1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000279 AC: 7 AN: 250630 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461438 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 727012

African (AFR) AF: 0.00 AC: 0 AN: 33448

American (AMR) AF: 0.000201 AC: 9 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.00 AC: 0 AN: 86206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111776

Other (OTH) AF: 0.00 AC: 0 AN: 60372

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000247 AC: 3

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	Uncertain	0.36
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Uncertain	0.090
CADD	Benign	22
DANN	Benign	0.94
DEOGEN2	Uncertain	0.49	T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.41	T
MetaSVM	Uncertain	0.27	D
MutationAssessor	Benign	1.8	L
PhyloP100		5.9
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.65
Sift	Benign	0.081	T
Sift4G	Uncertain	0.059	T
Polyphen		0.17	B
Vest4		0.51
MutPred		0.64		Gain of loop (P = 0.0312)
MVP		0.79
MPC		1.5
ClinPred		0.62	D
GERP RS		5.3
Varity_R		0.27
gMVP		0.54
Mutation Taster		=24/76	disease causing

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: rs757790458; hg19: chr4-42487567;