Genetic Variant NM_000704.3:c.1500+5G>T (chr19-35558357-C-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PP3_ModerateBP6_Very_StrongBS1BS2

The NM_000704.3(ATP4A):c.1500+5G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0197 in 1,607,458 control chromosomes in the GnomAD database, including 413 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.016 ( 33 hom., cov: 32)

Exomes 𝑓: 0.020 ( 380 hom. )

Consequence

ATP4A
NM_000704.3 splice_region, intron

Scores

Splicing: ADA: 0.9997

Clinical Significance

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

Conservation

PhyloP100: 2.65

Publications

2 publications found

Variant links:

Genes affected

ATP4A (HGNC:819): (ATPase H+/K+ transporting subunit alpha) The protein encoded by this gene belongs to a family of P-type cation-transporting ATPases. The gastric H+, K+-ATPase is a heterodimer consisting of a high molecular weight catalytic alpha subunit and a smaller but heavily glycosylated beta subunit. This enzyme is a proton pump that catalyzes the hydrolysis of ATP coupled with the exchange of H(+) and K(+) ions across the plasma membrane. It is also responsible for gastric acid secretion. This gene encodes a catalytic alpha subunit of the gastric H+, K+-ATPase. [provided by RefSeq, Jul 2008]

ATP4A links:

LINC01766 (HGNC:52556): (long intergenic non-protein coding RNA 1766)

LINC01766 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

BP6

Variant 19-35558357-C-A is Benign according to our data. Variant chr19-35558357-C-A is described in ClinVar as Benign. ClinVar VariationId is 1600838.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 = 0.0159 (2416/152270) while in subpopulation NFE AF = 0.0222 (1509/68000). AF 95% confidence interval is 0.0213. There are 33 homozygotes in GnomAd4. There are 1199 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 33 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000704.3. 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
	ATP4A	NM_000704.3	MANE Select	c.1500+5G>T		splice_region intron	N/A	NP_000695.2	P20648

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ATP4A	ENST00000262623.4	TSL:1 MANE Select	c.1500+5G>T	splice_region intron	N/A	ENSP00000262623.2	P20648
LINC01766	ENST00000638356.1	TSL:1	n.72+330C>A	intron	N/A
LINC01766	ENST00000702449.2		n.109+330C>A	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0159

AC:

2419

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00398

Gnomad AMI

AF:

0.0658

Gnomad AMR

AF:

0.0202

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00869

Gnomad FIN

AF:

0.0274

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0222

Gnomad OTH

AF:

0.0153

GnomAD2 exomes

AF:

0.0160

AC:

3793

AN:

236862

AF XY:

0.0160

show subpopulations

Gnomad AFR exome

AF:

0.00340

Gnomad AMR exome

AF:

0.0101

Gnomad ASJ exome

AF:

0.000512

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0291

Gnomad NFE exome

AF:

0.0238

Gnomad OTH exome

AF:

0.0176

GnomAD4 exome

AF:

0.0201

AC:

29219

AN:

1455188

Hom.:

380

Cov.:

AF XY:

0.0197

AC XY:

14279

AN XY:

723202

show subpopulations

African (AFR)

AF:

0.00329

AC:

110

AN:

33428

American (AMR)

AF:

0.0108

AC:

472

AN:

43598

Ashkenazi Jewish (ASJ)

AF:

0.00104

AC:

AN:

25928

East Asian (EAS)

AF:

0.00

AC:

AN:

39438

South Asian (SAS)

AF:

0.00621

AC:

529

AN:

85156

European-Finnish (FIN)

AF:

0.0300

AC:

1580

AN:

52712

Middle Eastern (MID)

AF:

0.0134

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.0230

AC:

25537

AN:

1109074

Other (OTH)

AF:

0.0148

AC:

887

AN:

60100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

1617

3234

4852

6469

8086

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

960

1920

2880

3840

4800

<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:

0.0159

AC:

2416

AN:

152270

Hom.:

Cov.:

AF XY:

0.0161

AC XY:

1199

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.00397

AC:

165

AN:

41568

American (AMR)

AF:

0.0201

AC:

308

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.000194

AC:

AN:

5164

South Asian (SAS)

AF:

0.00870

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0274

AC:

291

AN:

10614

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0222

AC:

1509

AN:

68000

Other (OTH)

AF:

0.0151

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

117

234

352

469

586

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.0200

Hom.:

Bravo

AF:

0.0144

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Benign

0.94

PhyloP100

2.6

Mutation Taster

=74/26

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.97

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

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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