NM_025153.3:c.3979C>G

Variant names:

• chr5-160565860-G-C
• rs1396994309
• NM_025153.3:c.3979C>G

Variant summary

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

The NM_025153.3(ATP10B):​c.3979C>G​(p.Leu1327Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,550 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: ATP10B NM_025153.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.34
• Publications: 4 publications found

Genes affected

ATP10B (HGNC:13543): (ATPase phospholipid transporting 10B (putative)) Enables glycosylceramide flippase activity and phosphatidylcholine flippase activity. Involved in lysosomal membrane organization. Located in endoplasmic reticulum. Is integral component of lysosomal membrane. Part of phospholipid-translocating ATPase complex. [provided by Alliance of Genome Resources, Apr 2022]

MIR3142HG (HGNC:51944): (MIR3142 host gene)

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=0.09674305).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP10B	NM_025153.3	c.3979C>G	p.Leu1327Val	missense_variant	Exon 26 of 26	ENST00000327245.10	NP_079429.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP10B	ENST00000327245.10	c.3979C>G	p.Leu1327Val	missense_variant	Exon 26 of 26	1	NM_025153.3	ENSP00000313600.5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152120 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000201 AC: 5 AN: 248494 AF XY: 0.0000148

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.0000871

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: 0.00000547 AC: 8 AN: 1461430 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727064

African (AFR) AF: 0.000120 AC: 4 AN: 33376

American (AMR) AF: 0.0000672 AC: 3 AN: 44628

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111874

Other (OTH) AF: 0.00 AC: 0 AN: 60352

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152120 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74294

African (AFR) AF: 0.0000241 AC: 1 AN: 41434

American (AMR) AF: 0.00 AC: 0 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000312 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 01, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3979C>G (p.L1327V) alteration is located in exon 26 (coding exon 22) of the ATP10B gene. This alteration results from a C to G substitution at nucleotide position 3979, causing the leucine (L) at amino acid position 1327 to be replaced by a valine (V). 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	0.072
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	9.6
DANN	Benign	0.60
DEOGEN2	Benign	0.0012	.;T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.66	T;T
M_CAP	Benign	0.0073	T
MetaRNN	Benign	0.097	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	.;L
PhyloP100		2.3
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.22	.;N
REVEL	Benign	0.032
Sift	Benign	0.21	.;T
Sift4G	Benign	0.20	.;T
Polyphen		0.50	.;P
Vest4		0.10
MutPred		0.29		.;Gain of ubiquitination at K1325 (P = 0.095);
MVP		0.40
MPC		0.17
ClinPred		0.027	T
GERP RS		2.9
Varity_R		0.047
gMVP		0.25
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1396994309; hg19: chr5-159992867; COSMIC: COSV100515481;