rs3112831

Variant names:

• chr1-94078678-T-C
• rs3112831
• NM_000350.3:c.1268A>G

Your query was ambiguous. Multiple possible variants found:

• chr1-94078678-T-C
• chr1-94078678-T-G

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000350.3(ABCA4):​c.1268A>G​(p.His423Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.295 in 1,610,992 control chromosomes in the GnomAD database, including 72,755 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H423Y) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.26 (5454 hom., cov: 28)
  • Exomes 𝑓: 0.30 (67301 hom.)
• Consequence: ABCA4 NM_000350.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16 O:1
• Conservation: PhyloP100: 2.40
• Publications: 68 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

LOC124904222 (HGNC:):

ACMG classification

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

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 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 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=0.035622448).
• BP6: Variant 1-94078678-T-C is Benign according to our data. Variant chr1-94078678-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 99040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.314 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.1268A>G	p.His423Arg	missense	Exon 10 of 50	NP_000341.2	P78363
	ABCA4	NM_001425324.1		c.1268A>G	p.His423Arg	missense	Exon 10 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.1268A>G	p.His423Arg	missense	Exon 10 of 50	ENSP00000359245.3	P78363
	ABCA4	ENST00000649773.1		c.1268A>G	p.His423Arg	missense	Exon 10 of 19	ENSP00000496882.1	A0A3B3IRV8

Frequencies

GnomAD3 genomes AF: 0.258 AC: 39029 AN: 151382 Hom.: 5443 Cov.: 28

Gnomad AFR AF: 0.163

Gnomad AMI AF: 0.239

Gnomad AMR AF: 0.279

Gnomad ASJ AF: 0.250

Gnomad EAS AF: 0.260

Gnomad SAS AF: 0.174

Gnomad FIN AF: 0.254

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.318

Gnomad OTH AF: 0.265

GnomAD2 exomes AF: 0.255 AC: 64225 AN: 251484 AF XY: 0.254

Gnomad AFR exome AF: 0.162

Gnomad AMR exome AF: 0.219

Gnomad ASJ exome AF: 0.234

Gnomad EAS exome AF: 0.246

Gnomad FIN exome AF: 0.250

Gnomad NFE exome AF: 0.308

Gnomad OTH exome AF: 0.271

GnomAD4 exome AF: 0.299 AC: 435950 AN: 1459492 Hom.: 67301 Cov.: 40 AF XY: 0.294 AC XY: 213617 AN XY: 726128

African (AFR) AF: 0.162 AC: 5426 AN: 33458

American (AMR) AF: 0.227 AC: 10171 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.237 AC: 6194 AN: 26120

East Asian (EAS) AF: 0.254 AC: 10073 AN: 39682

South Asian (SAS) AF: 0.167 AC: 14362 AN: 86226

European-Finnish (FIN) AF: 0.253 AC: 13511 AN: 53390

Middle Eastern (MID) AF: 0.171 AC: 982 AN: 5758

European-Non Finnish (NFE) AF: 0.323 AC: 358535 AN: 1109836

Other (OTH) AF: 0.277 AC: 16696 AN: 60308

GnomAD4 genome AF: 0.258 AC: 39076 AN: 151500 Hom.: 5454 Cov.: 28 AF XY: 0.254 AC XY: 18812 AN XY: 73986

African (AFR) AF: 0.164 AC: 6759 AN: 41300

American (AMR) AF: 0.280 AC: 4248 AN: 15188

Ashkenazi Jewish (ASJ) AF: 0.250 AC: 866 AN: 3462

East Asian (EAS) AF: 0.260 AC: 1334 AN: 5124

South Asian (SAS) AF: 0.175 AC: 838 AN: 4788

European-Finnish (FIN) AF: 0.254 AC: 2658 AN: 10454

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.318 AC: 21567 AN: 67884

Other (OTH) AF: 0.265 AC: 557 AN: 2098

Alfa AF: 0.293 Hom.: 25776

Bravo AF: 0.256

TwinsUK AF: 0.328 AC: 1216

ALSPAC AF: 0.304 AC: 1170

ESP6500AA AF: 0.165 AC: 729

ESP6500EA AF: 0.309 AC: 2661

ExAC AF: 0.255 AC: 30988

Asia WGS AF: 0.236 AC: 819 AN: 3478

EpiCase AF: 0.303

EpiControl AF: 0.304

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (6)
-	-	5	not specified (5)
-	-	1	ABCA4-related disorder (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	0.048
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	4.8
DANN	Benign	0.92
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.058	N
LIST_S2	Benign	0.077	T
MetaRNN	Benign	0.036	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-2.5	N
PhyloP100		2.4
PrimateAI	Benign	0.41	T
PROVEAN	Benign	2.1	N
REVEL	Uncertain	0.29
Sift	Benign	0.36	T
Sift4G	Benign	0.28	T
Polyphen		0.0	B
Vest4		0.038
MPC		0.10
ClinPred		0.014	T
GERP RS		5.5
Varity_R		0.076
gMVP		0.64
Mutation Taster		=72/28	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3112831; hg19: chr1-94544234; COSMIC: COSV64671966;