1-94113011-C-G

Variant names:

• chr1-94113011-C-G
• rs61751410
• NM_000350.3:c.122G>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_000350.3(ABCA4):​c.122G>C​(p.Trp41Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ABCA4 NM_000350.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.96
• Publications: 0 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a transmembrane_region Helical (size 20) in uniprot entity ABCA4_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_000350.3
• PM2: Very rare variant in population databases, with high coverage
• 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.

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.122G>C	p.Trp41Ser	missense	Exon 2 of 50	NP_000341.2
	ABCA4	NM_001425324.1		c.122G>C	p.Trp41Ser	missense	Exon 2 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.122G>C	p.Trp41Ser	missense	Exon 2 of 50	ENSP00000359245.3
	ABCA4	ENST00000649773.1		c.122G>C	p.Trp41Ser	missense	Exon 2 of 19	ENSP00000496882.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Uncertain	24
DANN	Benign	0.93
DEOGEN2	Uncertain	0.66	D
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.70	T
M_CAP	Pathogenic	0.48	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Benign	1.8	L
PhyloP100		6.0
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.2	D
REVEL	Pathogenic	0.77
Sift	Benign	0.50	T
Sift4G	Benign	0.60	T
Polyphen		0.97	D
Vest4		0.69
MutPred		0.53		Loss of catalytic residue at L39 (P = 0.0047)
MVP		0.98
MPC		0.57
ClinPred		0.76	D
GERP RS		5.9
Varity_R		0.60
gMVP		0.89
Mutation Taster		=19/81	disease causing

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: rs61751410; hg19: chr1-94578567;