chr1-94008772-T-C

Variant names:

• chr1-94008772-T-C
• rs4147857
• NM_000350.3:c.5814A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000350.3(ABCA4):​c.5814A>G​(p.Leu1938Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 1,613,452 control chromosomes in the GnomAD database, including 29,638 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3167 hom., cov: 31)
  • Exomes 𝑓: 0.19 (26471 hom.)
• Consequence: ABCA4 NM_000350.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18 O:1
• Conservation: PhyloP100: -0.130
• Publications: 33 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 1-94008772-T-C is Benign according to our data. Variant chr1-94008772-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 99407.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.13 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.236 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.5814A>G	p.Leu1938Leu	synonymous	Exon 41 of 50	NP_000341.2	P78363
	ABCA4	NM_001425324.1		c.5592A>G	p.Leu1864Leu	synonymous	Exon 40 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.5814A>G	p.Leu1938Leu	synonymous	Exon 41 of 50	ENSP00000359245.3	P78363
	ABCA4	ENST00000465352.1	TSL:5	n.230A>G		non_coding_transcript_exon	Exon 2 of 6

Frequencies

GnomAD3 genomes AF: 0.201 AC: 30566 AN: 151826 Hom.: 3152 Cov.: 31

Gnomad AFR AF: 0.240

Gnomad AMI AF: 0.136

Gnomad AMR AF: 0.208

Gnomad ASJ AF: 0.214

Gnomad EAS AF: 0.130

Gnomad SAS AF: 0.131

Gnomad FIN AF: 0.174

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.192

Gnomad OTH AF: 0.188

GnomAD2 exomes AF: 0.190 AC: 47731 AN: 251474 AF XY: 0.184

Gnomad AFR exome AF: 0.241

Gnomad AMR exome AF: 0.244

Gnomad ASJ exome AF: 0.205

Gnomad EAS exome AF: 0.127

Gnomad FIN exome AF: 0.177

Gnomad NFE exome AF: 0.192

Gnomad OTH exome AF: 0.189

GnomAD4 exome AF: 0.188 AC: 274047 AN: 1461508 Hom.: 26471 Cov.: 33 AF XY: 0.186 AC XY: 134952 AN XY: 727058

African (AFR) AF: 0.248 AC: 8308 AN: 33470

American (AMR) AF: 0.241 AC: 10777 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.207 AC: 5402 AN: 26134

East Asian (EAS) AF: 0.136 AC: 5402 AN: 39692

South Asian (SAS) AF: 0.135 AC: 11686 AN: 86252

European-Finnish (FIN) AF: 0.180 AC: 9593 AN: 53386

Middle Eastern (MID) AF: 0.174 AC: 1001 AN: 5766

European-Non Finnish (NFE) AF: 0.190 AC: 210737 AN: 1111710

Other (OTH) AF: 0.185 AC: 11141 AN: 60380

GnomAD4 genome AF: 0.202 AC: 30633 AN: 151944 Hom.: 3167 Cov.: 31 AF XY: 0.199 AC XY: 14746 AN XY: 74260

African (AFR) AF: 0.240 AC: 9952 AN: 41412

American (AMR) AF: 0.208 AC: 3178 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.214 AC: 742 AN: 3472

East Asian (EAS) AF: 0.131 AC: 674 AN: 5164

South Asian (SAS) AF: 0.131 AC: 630 AN: 4814

European-Finnish (FIN) AF: 0.174 AC: 1834 AN: 10560

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.192 AC: 13045 AN: 67940

Other (OTH) AF: 0.194 AC: 409 AN: 2108

Alfa AF: 0.198 Hom.: 10979

Bravo AF: 0.208

Asia WGS AF: 0.161 AC: 561 AN: 3478

EpiCase AF: 0.190

EpiControl AF: 0.189

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (4)
-	-	1	ABCA4-related disorder (1)
-	-	1	Age related macular degeneration 2 (1)
-	-	1	Cone-rod dystrophy 3 (1)
-	-	1	Cone-Rod Dystrophy, Recessive (1)
-	-	1	Macular degeneration (1)
-	-	1	Retinal dystrophy (1)
-	-	1	Retinitis pigmentosa 19 (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
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.4
DANN	Benign	0.52
PhyloP100		-0.13
Mutation Taster		=98/2	polymorphism (auto)

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: rs4147857; hg19: chr1-94474328; COSMIC: COSV64672046; COSMIC: COSV64672046;