chr1-94008290-G-A

Variant names:

• chr1-94008290-G-A
• rs56142141
• NM_000350.3:c.5843C>T
• ABCA4 p.Pro1948Leu

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000350.3(ABCA4):​c.5843C>T​(p.Pro1948Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0393 in 1,613,262 control chromosomes in the GnomAD database, including 1,534 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. P1948P) has been classified as Uncertain significance. The gene ABCA4 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.031 (107 hom., cov: 32)
  • Exomes 𝑓: 0.040 (1427 hom.)
• Consequence: ABCA4 NM_000350.3 missense
• Clinical Significance: Likely benign reviewed by expert panel U:1 B:12 O:1
• Conservation: PhyloP100: 2.29
• Publications: 20 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• severe early-childhood-onset retinal dystrophy

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, 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

Specifications for ABCA4 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -17 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000350.3
• 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 severe early-childhood-onset retinal dystrophy, retinitis pigmentosa, age related macular degeneration 2, retinitis pigmentosa 19, cone-rod dystrophy 3, ABCA4-related retinopathy, Stargardt disease, cone-rod dystrophy.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0034454763).
• BP6: Variant 1-94008290-G-A is Benign according to our data. Variant chr1-94008290-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 99413.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.031 (4724/152224) while in subpopulation NFE AF = 0.0452 (3075/68010). AF 95% confidence interval is 0.0439. There are 107 homozygotes in GnomAd4. There are 2259 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 107 AR,AD gene

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.5843C>T	p.Pro1948Leu	missense	Exon 42 of 50	NP_000341.2	P78363
	ABCA4	NM_001425324.1		c.5621C>T	p.Pro1874Leu	missense	Exon 41 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.5843C>T	p.Pro1948Leu	missense	Exon 42 of 50	ENSP00000359245.3	P78363
	ABCA4	ENST00000465352.1	TSL:5	n.259C>T		non_coding_transcript_exon	Exon 3 of 6

Frequencies

GnomAD3 genomes AF: 0.0311 AC: 4725 AN: 152106 Hom.: 107 Cov.: 32

Gnomad AFR AF: 0.00780

Gnomad AMI AF: 0.0549

Gnomad AMR AF: 0.0348

Gnomad ASJ AF: 0.0110

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00705

Gnomad FIN AF: 0.0565

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0452

Gnomad OTH AF: 0.0335

GnomAD2 exomes AF: 0.0314 AC: 7885 AN: 251428 AF XY: 0.0315

Gnomad AFR exome AF: 0.00775

Gnomad AMR exome AF: 0.0260

Gnomad ASJ exome AF: 0.0152

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0588

Gnomad NFE exome AF: 0.0438

Gnomad OTH exome AF: 0.0380

GnomAD4 exome AF: 0.0402 AC: 58669 AN: 1461038 Hom.: 1427 Cov.: 33 AF XY: 0.0393 AC XY: 28553 AN XY: 726844

African (AFR) AF: 0.00699 AC: 234 AN: 33478

American (AMR) AF: 0.0262 AC: 1173 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0148 AC: 387 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00774 AC: 668 AN: 86250

European-Finnish (FIN) AF: 0.0564 AC: 3012 AN: 53412

Middle Eastern (MID) AF: 0.0147 AC: 85 AN: 5768

European-Non Finnish (NFE) AF: 0.0459 AC: 51015 AN: 1111222

Other (OTH) AF: 0.0347 AC: 2093 AN: 60358

GnomAD4 genome AF: 0.0310 AC: 4724 AN: 152224 Hom.: 107 Cov.: 32 AF XY: 0.0303 AC XY: 2259 AN XY: 74436

African (AFR) AF: 0.00775 AC: 322 AN: 41548

American (AMR) AF: 0.0347 AC: 531 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0110 AC: 38 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.00705 AC: 34 AN: 4822

European-Finnish (FIN) AF: 0.0565 AC: 599 AN: 10596

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0452 AC: 3075 AN: 68010

Other (OTH) AF: 0.0331 AC: 70 AN: 2112

Alfa AF: 0.0379 Hom.: 237

Bravo AF: 0.0293

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.0434

EpiControl AF: 0.0451

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T
Eigen	Benign	0.0092
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0034	T
MetaSVM	Uncertain	0.044	D
MutationAssessor	Benign	2.0	M
PhyloP100		2.3
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.53	N
REVEL	Uncertain	0.31
Sift	Benign	0.10	T
Sift4G	Benign	0.19	T
Varity_R		0.068
gMVP		0.73
Mutation Taster		=93/7	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs56142141;

hg19: chr1-94473846;

COSMIC: COSV64673479;

COSMIC: COSV64673479;