rs4147831

Variant names:

• chr1-94078677-G-A
• rs4147831
• NM_000350.3:c.1269C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-94078677-G-A
• chr1-94078677-G-C
• chr1-94078677-G-T

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.1269C>T​(p.His423His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0819 in 1,608,676 control chromosomes in the GnomAD database, including 5,818 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.094 (773 hom., cov: 26)
  • Exomes 𝑓: 0.081 (5045 hom.)
• Consequence: ABCA4 NM_000350.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12 O:1
• Conservation: PhyloP100: -0.965
• Publications: 24 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 1-94078677-G-A is Benign according to our data. Variant chr1-94078677-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 99041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.965 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.129 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.1269C>T	p.His423His	synonymous	Exon 10 of 50	NP_000341.2
	ABCA4	NM_001425324.1		c.1269C>T	p.His423His	synonymous	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.1269C>T	p.His423His	synonymous	Exon 10 of 50	ENSP00000359245.3
	ABCA4	ENST00000649773.1		c.1269C>T	p.His423His	synonymous	Exon 10 of 19	ENSP00000496882.1

Frequencies

GnomAD3 genomes AF: 0.0939 AC: 14151 AN: 150748 Hom.: 775 Cov.: 26

Gnomad AFR AF: 0.132

Gnomad AMI AF: 0.0209

Gnomad AMR AF: 0.115

Gnomad ASJ AF: 0.0240

Gnomad EAS AF: 0.135

Gnomad SAS AF: 0.0908

Gnomad FIN AF: 0.0532

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0749

Gnomad OTH AF: 0.0749

GnomAD2 exomes AF: 0.0873 AC: 21948 AN: 251476 AF XY: 0.0842

Gnomad AFR exome AF: 0.132

Gnomad AMR exome AF: 0.123

Gnomad ASJ exome AF: 0.0289

Gnomad EAS exome AF: 0.122

Gnomad FIN exome AF: 0.0598

Gnomad NFE exome AF: 0.0740

Gnomad OTH exome AF: 0.0780

GnomAD4 exome AF: 0.0807 AC: 117653 AN: 1457812 Hom.: 5045 Cov.: 39 AF XY: 0.0801 AC XY: 58058 AN XY: 725258

African (AFR) AF: 0.129 AC: 4294 AN: 33372

American (AMR) AF: 0.121 AC: 5407 AN: 44594

Ashkenazi Jewish (ASJ) AF: 0.0294 AC: 765 AN: 26004

East Asian (EAS) AF: 0.134 AC: 5278 AN: 39474

South Asian (SAS) AF: 0.0883 AC: 7609 AN: 86216

European-Finnish (FIN) AF: 0.0578 AC: 3070 AN: 53124

Middle Eastern (MID) AF: 0.0415 AC: 238 AN: 5736

European-Non Finnish (NFE) AF: 0.0776 AC: 86068 AN: 1109154

Other (OTH) AF: 0.0819 AC: 4924 AN: 60138

GnomAD4 genome AF: 0.0939 AC: 14161 AN: 150864 Hom.: 773 Cov.: 26 AF XY: 0.0933 AC XY: 6867 AN XY: 73588

African (AFR) AF: 0.132 AC: 5419 AN: 41100

American (AMR) AF: 0.115 AC: 1732 AN: 15040

Ashkenazi Jewish (ASJ) AF: 0.0240 AC: 83 AN: 3464

East Asian (EAS) AF: 0.133 AC: 675 AN: 5068

South Asian (SAS) AF: 0.0896 AC: 426 AN: 4754

European-Finnish (FIN) AF: 0.0532 AC: 546 AN: 10264

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0749 AC: 5085 AN: 67864

Other (OTH) AF: 0.0802 AC: 169 AN: 2106

Alfa AF: 0.0804 Hom.: 2587

Bravo AF: 0.101

Asia WGS AF: 0.129 AC: 447 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (4)
-	-	3	not specified (3)
-	-	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
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.11
DANN	Benign	0.39
PhyloP100		-0.96
Mutation Taster		=100/0	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

Other links and lift over

dbSNP: rs4147831; hg19: chr1-94544233; COSMIC: COSV64672022;