Genetic Variant NM_016361.5:c.652C>T (chr1-147654322-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_016361.5(ACP6):c.652C>T(p.Arg218Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0149 in 1,613,876 control chromosomes in the GnomAD database, including 225 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R218R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.010 ( 14 hom., cov: 32)

Exomes 𝑓: 0.015 ( 211 hom. )

Consequence

ACP6
NM_016361.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.39

Publications

13 publications found

Variant links:

Genes affected

ACP6 (HGNC:29609): (acid phosphatase 6, lysophosphatidic) This gene encodes a member of the histidine acid phosphatase protein family. The encoded protein hydrolyzes lysophosphatidic acid, which is involved in G protein-coupled receptor signaling, lipid raft modulation, and in balancing lipid composition within the cell. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2016]

ACP6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004639417).

BP6

Variant 1-147654322-G-A is Benign according to our data. Variant chr1-147654322-G-A is described in ClinVar as Benign. ClinVar VariationId is 218733.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0105 (1593/152210) while in subpopulation NFE AF = 0.0172 (1171/68010). AF 95% confidence interval is 0.0164. There are 14 homozygotes in GnomAd4. There are 739 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 14 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016361.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ACP6	NM_016361.5	MANE Select	c.652C>T	p.Arg218Trp	missense	Exon 6 of 10	NP_057445.4
ACP6	NM_001323625.2		c.652C>T	p.Arg218Trp	missense	Exon 6 of 9	NP_001310554.1
ACP6	NR_136633.2		n.1128C>T		non_coding_transcript_exon	Exon 6 of 9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ACP6	ENST00000583509.7	TSL:1 MANE Select	c.652C>T	p.Arg218Trp	missense	Exon 6 of 10	ENSP00000463574.1	Q9NPH0-1
ACP6	ENST00000392988.6	TSL:1	c.523C>T	p.Arg175Trp	missense	Exon 5 of 6	ENSP00000376714.3	A0A0A0MS36
ACP6	ENST00000613673.4	TSL:1	n.887C>T		non_coding_transcript_exon	Exon 6 of 8

Frequencies

GnomAD3 genomes

AF:

0.0105

AC:

1593

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00287

Gnomad AMI

AF:

0.0428

Gnomad AMR

AF:

0.00760

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00870

Gnomad FIN

AF:

0.00727

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0172

Gnomad OTH

AF:

0.0100

GnomAD2 exomes

AF:

0.0106

AC:

2671

AN:

251214

AF XY:

0.0114

show subpopulations

Gnomad AFR exome

AF:

0.00375

Gnomad AMR exome

AF:

0.00611

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00737

Gnomad NFE exome

AF:

0.0158

Gnomad OTH exome

AF:

0.0124

GnomAD4 exome

AF:

0.0153

AC:

22421

AN:

1461666

Hom.:

211

Cov.:

AF XY:

0.0153

AC XY:

11145

AN XY:

727170

show subpopulations

African (AFR)

AF:

0.00266

AC:

AN:

33458

American (AMR)

AF:

0.00682

AC:

305

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.000612

AC:

AN:

26124

East Asian (EAS)

AF:

0.000378

AC:

AN:

39698

South Asian (SAS)

AF:

0.0126

AC:

1091

AN:

86246

European-Finnish (FIN)

AF:

0.00742

AC:

396

AN:

53374

Middle Eastern (MID)

AF:

0.0168

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0177

AC:

19642

AN:

1111918

Other (OTH)

AF:

0.0128

AC:

770

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

1046

2092

3139

4185

5231

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

764

1528

2292

3056

3820

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0105

AC:

1593

AN:

152210

Hom.:

Cov.:

AF XY:

0.00993

AC XY:

739

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.00287

AC:

119

AN:

41528

American (AMR)

AF:

0.00759

AC:

116

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.00891

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00727

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0172

AC:

1171

AN:

68010

Other (OTH)

AF:

0.00994

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

166

249

332

415

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0136

Hom.:

Bravo

AF:

0.00976

TwinsUK

AF:

0.0224

AC:

ALSPAC

AF:

0.0228

AC:

ESP6500AA

AF:

0.00318

AC:

ESP6500EA

AF:

0.0167

AC:

144

ExAC

AF:

0.0109

AC:

1319

EpiCase

AF:

0.0155

EpiControl

AF:

0.0162

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.48

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.085

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.77

LIST_S2

Uncertain

0.92

MetaRNN

Benign

0.0046

MetaSVM

Benign

-1.0

MutationAssessor

Pathogenic

2.9

PhyloP100

2.4

PrimateAI

Benign

0.42

REVEL

Benign

0.18

Sift4G

Uncertain

0.023

Polyphen

1.0

Vest4

0.15

ClinPred

0.032

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.37

gMVP

0.72

Mutation Taster

=84/16

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over