17-69250524-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_172232.4(ABCA5):c.4633C>T(p.Arg1545Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000104 in 1,600,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

ABCA5
NM_172232.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.51

Publications

1 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: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.18532139).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA5	NM_172232.4 link	c.4633C>T	p.Arg1545Cys	missense_variant	Exon 36 of 39	ENST00000392676.8	NP_758424.1	Q8WWZ7-1
ABCA5	NM_018672.5 link	c.4633C>T	p.Arg1545Cys	missense_variant	Exon 35 of 38		NP_061142.2	Q8WWZ7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA5	ENST00000392676.8 link	c.4633C>T	p.Arg1545Cys	missense_variant	Exon 36 of 39	1	NM_172232.4	ENSP00000376443.2		Q8WWZ7-1

Frequencies

GnomAD3 genomes

AF:

0.0000724

AC:

AN:

151858

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

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:

0.000284

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000442

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000504

AC:

AN:

238322

AF XY:

0.0000388

show subpopulations

Gnomad AFR exome

AF:

0.000255

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000466

Gnomad NFE exome

AF:

0.0000547

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000107

AC:

155

AN:

1448994

Hom.:

Cov.:

AF XY:

0.0000916

AC XY:

AN XY:

720618

show subpopulations

African (AFR)

AF:

0.0000918

AC:

AN:

32676

American (AMR)

AF:

0.00

AC:

AN:

41832

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25760

East Asian (EAS)

AF:

0.00

AC:

AN:

39062

South Asian (SAS)

AF:

0.0000120

AC:

AN:

83568

European-Finnish (FIN)

AF:

0.000113

AC:

AN:

53140

Middle Eastern (MID)

AF:

0.000175

AC:

AN:

5718

European-Non Finnish (NFE)

AF:

0.000127

AC:

141

AN:

1107410

Other (OTH)

AF:

0.0000501

AC:

AN:

59828

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.435

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000724

AC:

AN:

151858

Hom.:

Cov.:

AF XY:

0.0000944

AC XY:

AN XY:

74146

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41330

American (AMR)

AF:

0.00

AC:

AN:

15234

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.000284

AC:

AN:

10558

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000442

AC:

AN:

67948

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.0000529

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 25, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.4633C>T (p.R1545C) alteration is located in exon 35 (coding exon 35) of the ABCA5 gene. This alteration results from a C to T substitution at nucleotide position 4633, causing the arginine (R) at amino acid position 1545 to be replaced by a cysteine (C). 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

0.081

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.16

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

T;T;.

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.79

.;T;T

M_CAP

Benign

0.031

MetaRNN

Benign

0.19

T;T;T

MetaSVM

Benign

-0.51

MutationAssessor

Benign

0.90

L;L;.

PhyloP100

3.5

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.90

N;.;.

REVEL

Uncertain

0.39

Sift

Benign

0.17

T;.;.

Sift4G

Benign

0.18

T;T;.

Polyphen

0.98

D;D;.

Vest4

0.27

MVP

0.89

MPC

0.064

ClinPred

0.068

GERP RS

6.1

Varity_R

0.070

gMVP

0.60

Mutation Taster

=94/6

polymorphism

(source)

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

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17-69250524-G-A

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