17-69253570-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_172232.4(ABCA5):c.4415+3G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0186 in 1,604,852 control chromosomes in the GnomAD database, including 360 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.012 ( 23 hom., cov: 32)

Exomes 𝑓: 0.019 ( 337 hom. )

Consequence

ABCA5
NM_172232.4 splice_region, intron

Scores

Splicing: ADA: 0.00006409

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.291

Publications

7 publications found

Variant links:

Genes affected

ABCA5 (HGNC:35): (ATP binding cassette subfamily A member 5) The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intracellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, and White). This encoded protein is a member of the ABC1 subfamily. Members of the ABC1 subfamily comprise the only major ABC subfamily found exclusively in multicellular eukaryotes. This gene is clustered among 4 other ABC1 family members on 17q24, but neither the substrate nor the function of this gene is known. Alternative splicing of this gene results in several transcript variants; however, not all variants have been fully described. [provided by RefSeq, Jul 2008]

ABCA5 Gene-Disease associations (from GenCC):

gingival fibromatosis-hypertrichosis syndrome
Inheritance: AD, AR Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, G2P, Ambry Genetics
ventricular tachycardia, familial
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ABCA5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.41).

BP6

Variant 17-69253570-C-T is Benign according to our data. Variant chr17-69253570-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3037281.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0119 (1816/152262) while in subpopulation NFE AF = 0.0212 (1443/67998). AF 95% confidence interval is 0.0203. There are 23 homozygotes in GnomAd4. There are 785 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 23 Unknown,AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA5	NM_172232.4 link	c.4415+3G>A		splice_region_variant, intron_variant	Intron 34 of 38	ENST00000392676.8	NP_758424.1	Q8WWZ7-1
ABCA5	NM_018672.5 link	c.4415+3G>A		splice_region_variant, intron_variant	Intron 33 of 37		NP_061142.2	Q8WWZ7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA5	ENST00000392676.8 link	c.4415+3G>A		splice_region_variant, intron_variant	Intron 34 of 38	1	NM_172232.4	ENSP00000376443.2		Q8WWZ7-1

Frequencies

GnomAD3 genomes

AF:

0.0119

AC:

1816

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00449

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00831

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00349

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0212

Gnomad OTH

AF:

0.00955

GnomAD2 exomes

AF:

0.0107

AC:

2692

AN:

250930

AF XY:

0.0110

show subpopulations

Gnomad AFR exome

AF:

0.00375

Gnomad AMR exome

AF:

0.00448

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00527

Gnomad NFE exome

AF:

0.0198

Gnomad OTH exome

AF:

0.0116

GnomAD4 exome

AF:

0.0193

AC:

28032

AN:

1452590

Hom.:

337

Cov.:

AF XY:

0.0186

AC XY:

13427

AN XY:

723364

show subpopulations

African (AFR)

AF:

0.00279

AC:

AN:

33276

American (AMR)

AF:

0.00503

AC:

225

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.000154

AC:

AN:

26058

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39594

South Asian (SAS)

AF:

0.00115

AC:

AN:

86052

European-Finnish (FIN)

AF:

0.00659

AC:

352

AN:

53402

Middle Eastern (MID)

AF:

0.00192

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.0238

AC:

26268

AN:

1103662

Other (OTH)

AF:

0.0163

AC:

979

AN:

60098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

1104

2208

3313

4417

5521

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0119

AC:

1816

AN:

152262

Hom.:

Cov.:

AF XY:

0.0105

AC XY:

785

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.00448

AC:

186

AN:

41564

American (AMR)

AF:

0.00830

AC:

127

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.000415

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00349

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0212

AC:

1443

AN:

67998

Other (OTH)

AF:

0.00945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

195

293

390

488

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0181

Hom.:

Bravo

AF:

0.0126

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0199

EpiControl

AF:

0.0179

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

ABCA5-related disorder

Benign:1

Mar 06, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Benign

0.63

PhyloP100

0.29

Mutation Taster

=83/17

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000064

dbscSNV1_RF

Benign

0.0

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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17-69253570-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over