1-94112992-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000350.3(ABCA4):c.141A>G(p.Pro47Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.998 in 1,613,766 control chromosomes in the GnomAD database, including 803,477 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.99 ( 74421 hom., cov: 31)

Exomes 𝑓: 1.0 ( 729056 hom. )

Consequence

ABCA4
NM_000350.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -2.25

Publications

24 publications found

Variant links:

Genes affected

ABCA4 (HGNC:34): (ATP binding cassette subfamily A member 4) 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, White). This 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 protein is a retina-specific ABC transporter with N-retinylidene-PE as a substrate. It is expressed exclusively in retina photoreceptor cells, and the gene product mediates transport of an essental molecule, all-trans-retinal aldehyde (atRAL), across the photoreceptor cell membrane. Mutations in this gene are found in patients diagnosed with Stargardt disease, a form of juvenile-onset macular degeneration. Mutations in this gene are also associated with retinitis pigmentosa-19, cone-rod dystrophy type 3, early-onset severe retinal dystrophy, fundus flavimaculatus, and macular degeneration age-related 2. [provided by RefSeq, Sep 2019]

ABCA4 Gene-Disease associations (from GenCC):

ABCA4-related retinopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
cone-rod dystrophy 3
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
severe early-childhood-onset retinal dystrophy
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Ambry Genetics
retinitis pigmentosa 19
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
cone-rod dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
retinitis pigmentosa
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Stargardt disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ABCA4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant 1-94112992-T-C is Benign according to our data. Variant chr1-94112992-T-C is described in ClinVar as Benign. ClinVar VariationId is 166618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.26 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000350.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA4	NM_000350.3	MANE Select	c.141A>G	p.Pro47Pro	synonymous	Exon 2 of 50	NP_000341.2
	ABCA4	NM_001425324.1		c.141A>G	p.Pro47Pro	synonymous	Exon 2 of 49	NP_001412253.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA4	ENST00000370225.4	TSL:1 MANE Select	c.141A>G	p.Pro47Pro	synonymous	Exon 2 of 50	ENSP00000359245.3
	ABCA4	ENST00000649773.1		c.141A>G	p.Pro47Pro	synonymous	Exon 2 of 19	ENSP00000496882.1

Frequencies

GnomAD3 genomes

AF:

0.989

AC:

150416

AN:

152160

Hom.:

74372

Cov.:

show subpopulations

Gnomad AFR

AF:

0.960

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

0.995

Gnomad ASJ

AF:

1.00

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

0.999

Gnomad FIN

AF:

1.00

Gnomad MID

AF:

1.00

Gnomad NFE

AF:

1.00

Gnomad OTH

AF:

0.991

GnomAD2 exomes

AF:

0.997

AC:

250709

AN:

251442

AF XY:

0.998

show subpopulations

Gnomad AFR exome

AF:

0.959

Gnomad AMR exome

AF:

0.998

Gnomad ASJ exome

AF:

1.00

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

1.00

Gnomad NFE exome

AF:

1.00

Gnomad OTH exome

AF:

1.00

GnomAD4 exome

AF:

0.999

AC:

1459772

AN:

1461488

Hom.:

729056

Cov.:

AF XY:

0.999

AC XY:

726343

AN XY:

727068

show subpopulations

African (AFR)

AF:

0.958

AC:

32071

AN:

33470

American (AMR)

AF:

0.998

AC:

44636

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

26136

AN:

26136

East Asian (EAS)

AF:

1.00

AC:

39695

AN:

39696

South Asian (SAS)

AF:

1.00

AC:

86224

AN:

86244

European-Finnish (FIN)

AF:

1.00

AC:

53416

AN:

53416

Middle Eastern (MID)

AF:

0.999

AC:

5764

AN:

5768

European-Non Finnish (NFE)

AF:

1.00

AC:

1111620

AN:

1111660

Other (OTH)

AF:

0.997

AC:

60210

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

175

262

350

437

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21664

43328

64992

86656

108320

<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:

0.988

AC:

150524

AN:

152278

Hom.:

74421

Cov.:

AF XY:

0.988

AC XY:

73599

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.960

AC:

39865

AN:

41514

American (AMR)

AF:

0.995

AC:

15232

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

3472

AN:

3472

East Asian (EAS)

AF:

1.00

AC:

5178

AN:

5178

South Asian (SAS)

AF:

0.999

AC:

4827

AN:

4830

European-Finnish (FIN)

AF:

1.00

AC:

10616

AN:

10616

Middle Eastern (MID)

AF:

1.00

AC:

294

AN:

294

European-Non Finnish (NFE)

AF:

1.00

AC:

68032

AN:

68040

Other (OTH)

AF:

0.991

AC:

2096

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

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

914

1828

2742

3656

4570

<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:

0.996

Hom.:

208779

Bravo

AF:

0.987

Asia WGS

AF:

0.996

AC:

3465

AN:

3478

EpiCase

AF:

1.00

EpiControl

AF:

1.00

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Age related macular degeneration 2 (1)

Cone-rod dystrophy 3 (1)

not specified (1)

Retinitis pigmentosa 19 (1)

Severe early-childhood-onset retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.36

(source)

DANN

Benign

0.38

PhyloP100

-2.3

Mutation Taster

=77/23

polymorphism (auto)

(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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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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over