15-49987465-T-C

Position:

• chr15-49987465-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_024837.4(ATP8B4):​c.674A>G​(p.Asn225Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.235 in 1,613,206 control chromosomes in the GnomAD database, including 47,009 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.28 (6255 hom., cov: 32)
  • Exomes 𝑓: 0.23 (40754 hom.)
• Consequence: ATP8B4 NM_024837.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.184

Genes affected

ATP8B4 (HGNC:13536): (ATPase phospholipid transporting 8B4 (putative)) This gene encodes a member of the cation transport ATPase (P-type) family and type IV subfamily. The encoded protein is involved in phospholipid transport in the cell membrane. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2013]

ATP8B4 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0010026991).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.373 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP8B4	NM_024837.4	c.674A>G	p.Asn225Ser	missense_variant	10/28	ENST00000284509.11	NP_079113.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP8B4	ENST00000284509.11	c.674A>G	p.Asn225Ser	missense_variant	10/28	5	NM_024837.4	ENSP00000284509.6

Frequencies

GnomAD3 genomes AF: 0.276 AC: 41980 AN: 151922 Hom.: 6257 Cov.: 32

Gnomad AFR AF: 0.379

Gnomad AMI AF: 0.363

Gnomad AMR AF: 0.214

Gnomad ASJ AF: 0.0964

Gnomad EAS AF: 0.341

Gnomad SAS AF: 0.210

Gnomad FIN AF: 0.330

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.230

Gnomad OTH AF: 0.215

GnomAD3 exomes AF: 0.247 AC: 61824 AN: 250714 Hom.: 8226 AF XY: 0.241 AC XY: 32673 AN XY: 135496

Gnomad AFR exome AF: 0.383

Gnomad AMR exome AF: 0.222

Gnomad ASJ exome AF: 0.0975

Gnomad EAS exome AF: 0.352

Gnomad SAS exome AF: 0.210

Gnomad FIN exome AF: 0.323

Gnomad NFE exome AF: 0.228

Gnomad OTH exome AF: 0.211

GnomAD4 exome AF: 0.231 AC: 337618 AN: 1461166 Hom.: 40754 Cov.: 33 AF XY: 0.230 AC XY: 167288 AN XY: 726872

Gnomad4 AFR exome AF: 0.383

Gnomad4 AMR exome AF: 0.221

Gnomad4 ASJ exome AF: 0.0968

Gnomad4 EAS exome AF: 0.361

Gnomad4 SAS exome AF: 0.207

Gnomad4 FIN exome AF: 0.313

Gnomad4 NFE exome AF: 0.224

Gnomad4 OTH exome AF: 0.222

GnomAD4 genome AF: 0.276 AC: 42004 AN: 152040 Hom.: 6255 Cov.: 32 AF XY: 0.278 AC XY: 20681 AN XY: 74326

Gnomad4 AFR AF: 0.378

Gnomad4 AMR AF: 0.214

Gnomad4 ASJ AF: 0.0964

Gnomad4 EAS AF: 0.341

Gnomad4 SAS AF: 0.210

Gnomad4 FIN AF: 0.330

Gnomad4 NFE AF: 0.230

Gnomad4 OTH AF: 0.215

Alfa AF: 0.224 Hom.: 8605

Bravo AF: 0.271

TwinsUK AF: 0.225 AC: 836

ALSPAC AF: 0.206 AC: 794

ESP6500AA AF: 0.378 AC: 1661

ESP6500EA AF: 0.217 AC: 1866

ExAC AF: 0.251 AC: 30416

Asia WGS AF: 0.271 AC: 940 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	2.1
DANN	Benign	0.82
DEOGEN2	Benign	0.086	T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.76	D
LIST_S2	Uncertain	0.89	D;.
MetaRNN	Benign	0.0010	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.45	N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.60	N;N
REVEL	Benign	0.13
Sift	Benign	0.32	T;T
Sift4G	Benign	0.24	T;T
Polyphen		0.0	B;B
Vest4		0.057
MPC		0.045
ClinPred		0.0017	T
GERP RS		-2.2
Varity_R		0.049
gMVP		0.29

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: rs16963151; hg19: chr15-50279662; COSMIC: COSV52714235; COSMIC: COSV52714235;