rs201117452

Variant names:

• chr1-94078652-C-G
• rs201117452
• NM_000350.3:c.1294G>C

Your query was ambiguous. Multiple possible variants found:

• chr1-94078652-C-G
• chr1-94078652-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_000350.3(ABCA4):​c.1294G>C​(p.Glu432Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000734 in 1,362,088 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E432K) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 26)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: ABCA4 NM_000350.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.83
• Publications: 0 publications found

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

LOC124904222 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000350.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 578 curated pathogenic missense variants (we use a threshold of 10). The gene has 28 curated benign missense variants. Gene score misZ: -0.65813 (below the threshold of 3.09). Trascript score misZ: 1.3628 (below the threshold of 3.09). GenCC associations: The gene is linked to cone-rod dystrophy 3, retinitis pigmentosa 19, ABCA4-related retinopathy, severe early-childhood-onset retinal dystrophy, cone-rod dystrophy, Stargardt disease, retinitis pigmentosa.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA4	NM_000350.3	c.1294G>C	p.Glu432Gln	missense_variant	Exon 10 of 50	ENST00000370225.4	NP_000341.2
ABCA4	NM_001425324.1	c.1294G>C	p.Glu432Gln	missense_variant	Exon 10 of 49		NP_001412253.1
LOC124904222	XR_007066231.1	n.203-5077C>G		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4	c.1294G>C	p.Glu432Gln	missense_variant	Exon 10 of 50	1	NM_000350.3	ENSP00000359245.3
ABCA4	ENST00000649773.1	c.1294G>C	p.Glu432Gln	missense_variant	Exon 10 of 19			ENSP00000496882.1

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome AF: 7.34e-7 AC: 1 AN: 1362088 Hom.: 0 Cov.: 38 AF XY: 0.00000148 AC XY: 1 AN XY: 676196

African (AFR) AF: 0.00 AC: 0 AN: 30944

American (AMR) AF: 0.00 AC: 0 AN: 41484

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22382

East Asian (EAS) AF: 0.00 AC: 0 AN: 30564

South Asian (SAS) AF: 0.00 AC: 0 AN: 85460

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44804

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5272

European-Non Finnish (NFE) AF: 9.55e-7 AC: 1 AN: 1047340

Other (OTH) AF: 0.00 AC: 0 AN: 53838

GnomAD4 genome Cov.: 26

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T;.
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.87	D;T
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.63	D;D
MetaSVM	Uncertain	-0.052	T
MutationAssessor	Benign	1.9	L;.
PhyloP100		3.8
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.5	N;.
REVEL	Pathogenic	0.66
Sift	Benign	0.19	T;.
Sift4G	Benign	0.19	T;.
Polyphen		0.57	P;.
Vest4		0.45
MutPred		0.40		Gain of catalytic residue at E432 (P = 0.0402);Gain of catalytic residue at E432 (P = 0.0402);
MVP		0.86
MPC		0.18
ClinPred		0.85	D
GERP RS		4.6
Varity_R		0.19
gMVP		0.80
Mutation Taster		=20/80	disease causing

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

Other links and lift over

dbSNP: rs201117452; hg19: chr1-94544208;