6-138907513-T-A

Variant names:

• chr6-138907513-T-A
• rs1779738359
• NM_001286611.2:c.2304A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001286611.2(REPS1):​c.2304A>T​(p.Glu768Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,280 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E768K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: REPS1 NM_001286611.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.59
• Publications: 0 publications found

Genes affected

REPS1 (HGNC:15578): (RALBP1 associated Eps domain containing 1) This gene encodes a signaling adaptor protein with two EH domains that interacts with proteins that participate in signaling, endocytosis and cytoskeletal changes. The encoded protein has been found in association with intersectin 1 and Src homology 3-domain growth factor receptor-bound 2-like (endophilin) interacting protein 1 when intersectin 1 was isolated from clathrin-coated pits. The encoded protein has also been shown to interact with amphiphysin, a cytoplasmic protein at the surface of synaptic vesicles. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2014]

REPS1 Gene-Disease associations (from GenCC):

• neurodegeneration with brain iron accumulation 7

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20201501).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001286611.2. 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
	REPS1	NM_001286611.2	MANE Select	c.2304A>T	p.Glu768Asp	missense	Exon 19 of 20	NP_001273540.1	Q96D71-1
	REPS1	NM_031922.5		c.2301A>T	p.Glu767Asp	missense	Exon 19 of 20	NP_114128.3
	REPS1	NM_001128617.3		c.2223A>T	p.Glu741Asp	missense	Exon 18 of 19	NP_001122089.1	Q96D71-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	REPS1	ENST00000450536.7	TSL:1 MANE Select	c.2304A>T	p.Glu768Asp	missense	Exon 19 of 20	ENSP00000392065.2	Q96D71-1
	REPS1	ENST00000258062.9	TSL:1	c.2301A>T	p.Glu767Asp	missense	Exon 19 of 20	ENSP00000258062.5	Q96D71-3
	REPS1	ENST00000409812.6	TSL:1	c.2031A>T	p.Glu677Asp	missense	Exon 16 of 17	ENSP00000386699.2	Q96D71-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459280 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 726194

African (AFR) AF: 0.00 AC: 0 AN: 33428

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.00 AC: 0 AN: 86202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109734

Other (OTH) AF: 0.0000166 AC: 1 AN: 60296

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.093	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.072	T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.0	L
PhyloP100		2.6
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.23
Sift	Benign	0.060	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.67
MutPred		0.12		Loss of MoRF binding (P = 0.1334)
MVP		0.18
MPC		0.85
ClinPred		0.95	D
GERP RS		4.8
Varity_R		0.24
gMVP		0.36
Mutation Taster		=80/20	polymorphism

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: rs1779738359; hg19: chr6-139228650;