rs61750126

Variant names:

• chr1-94040048-A-C
• rs61750126
• NM_000350.3:c.3602T>G

Your query was ambiguous. Multiple possible variants found:

• chr1-94040048-A-C
• chr1-94040048-A-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000350.3(ABCA4):​c.3602T>G​(p.Leu1201Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00498 in 1,603,546 control chromosomes in the GnomAD database, including 369 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L1201L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.027 (212 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (157 hom.)
• Consequence: ABCA4 NM_000350.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:15 O:1
• Conservation: PhyloP100: 5.03
• Publications: 26 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
• age related macular degeneration 2

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0025280416).
• BP6: Variant 1-94040048-A-C is Benign according to our data. Variant chr1-94040048-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 7903.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0909 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA4	NM_000350.3	MANE Select	c.3602T>G	p.Leu1201Arg	missense	Exon 24 of 50	NP_000341.2	P78363
	ABCA4	NM_001425324.1		c.3380T>G	p.Leu1127Arg	missense	Exon 23 of 49	NP_001412253.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA4	ENST00000370225.4	TSL:1 MANE Select	c.3602T>G	p.Leu1201Arg	missense	Exon 24 of 50	ENSP00000359245.3	P78363

Frequencies

GnomAD3 genomes AF: 0.0266 AC: 4043 AN: 152052 Hom.: 211 Cov.: 32

Gnomad AFR AF: 0.0936

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00707

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.0182

GnomAD2 exomes AF: 0.00667 AC: 1566 AN: 234950 AF XY: 0.00499

Gnomad AFR exome AF: 0.0954

Gnomad AMR exome AF: 0.00386

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00463

GnomAD4 exome AF: 0.00272 AC: 3943 AN: 1451376 Hom.: 157 Cov.: 31 AF XY: 0.00242 AC XY: 1741 AN XY: 720738

African (AFR) AF: 0.0964 AC: 3218 AN: 33396

American (AMR) AF: 0.00438 AC: 192 AN: 43804

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25752

East Asian (EAS) AF: 0.00 AC: 0 AN: 39600

South Asian (SAS) AF: 0.000226 AC: 19 AN: 84078

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52690

Middle Eastern (MID) AF: 0.00400 AC: 23 AN: 5754

European-Non Finnish (NFE) AF: 0.000127 AC: 140 AN: 1106314

Other (OTH) AF: 0.00585 AC: 351 AN: 59988

GnomAD4 genome AF: 0.0266 AC: 4046 AN: 152170 Hom.: 212 Cov.: 32 AF XY: 0.0259 AC XY: 1929 AN XY: 74404

African (AFR) AF: 0.0934 AC: 3875 AN: 41504

American (AMR) AF: 0.00707 AC: 108 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000828 AC: 4 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 67986

Other (OTH) AF: 0.0180 AC: 38 AN: 2110

Alfa AF: 0.00817 Hom.: 186

Bravo AF: 0.0294

ESP6500AA AF: 0.0935 AC: 412

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00808 AC: 980

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (5)
-	-	3	not specified (3)
-	-	2	Severe early-childhood-onset retinal dystrophy (2)
-	-	1	ABCA4-related disorder (1)
1	-	-	Cone-rod dystrophy 3 (1)
-	-	1	Cone-Rod Dystrophy, Recessive (1)
-	-	1	Macular degeneration (1)
-	-	1	Retinal dystrophy (1)
-	-	1	Retinitis Pigmentosa, Recessive (1)
-	-	1	Stargardt Disease, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.33	T
Eigen	Benign	0.023
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	1.6	L
PhyloP100		5.0
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.71	N
REVEL	Uncertain	0.56
Sift	Benign	0.23	T
Sift4G	Benign	0.51	T
Polyphen		0.031	B
Vest4		0.74
MVP		0.94
MPC		0.51
ClinPred		0.028	T
GERP RS		5.5
Varity_R		0.29
gMVP		0.59
Mutation Taster		=79/21	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs61750126; hg19: chr1-94505604; COSMIC: COSV64674671;