NM_001286611.2:c.338C>A

Variant names:

• chr6-138945637-G-T
• rs201191394
• NM_001286611.2:c.338C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP5 BP4

The NM_001286611.2(REPS1):​c.338C>A​(p.Ala113Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000189 in 1,612,980 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: REPS1 NM_001286611.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 8.03
• Publications: 4 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.

• PP5: Variant 6-138945637-G-T is Pathogenic according to our data. Variant chr6-138945637-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 503504.
• BP4: Computational evidence support a benign effect (MetaRNN=0.053376377). . Strength limited to SUPPORTING due to the PP5.

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.338C>A	p.Ala113Glu	missense	Exon 3 of 20	NP_001273540.1
	REPS1	NM_031922.5		c.338C>A	p.Ala113Glu	missense	Exon 3 of 20	NP_114128.3
	REPS1	NM_001128617.3		c.338C>A	p.Ala113Glu	missense	Exon 3 of 19	NP_001122089.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	REPS1	ENST00000450536.7	TSL:1 MANE Select	c.338C>A	p.Ala113Glu	missense	Exon 3 of 20	ENSP00000392065.2
	REPS1	ENST00000258062.9	TSL:1	c.338C>A	p.Ala113Glu	missense	Exon 3 of 20	ENSP00000258062.5
	REPS1	ENST00000409812.6	TSL:1	c.338C>A	p.Ala113Glu	missense	Exon 3 of 17	ENSP00000386699.2

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000124 AC: 31 AN: 250238 AF XY: 0.000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000188 AC: 275 AN: 1460790 Hom.: 0 Cov.: 31 AF XY: 0.000161 AC XY: 117 AN XY: 726652

African (AFR) AF: 0.0000299 AC: 1 AN: 33424

American (AMR) AF: 0.000225 AC: 10 AN: 44494

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39652

South Asian (SAS) AF: 0.0000349 AC: 3 AN: 86034

European-Finnish (FIN) AF: 0.000187 AC: 10 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.000211 AC: 234 AN: 1111592

Other (OTH) AF: 0.000282 AC: 17 AN: 60326

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152190 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74350

African (AFR) AF: 0.0000724 AC: 3 AN: 41442

American (AMR) AF: 0.000131 AC: 2 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4832

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000173 Hom.: 0

Bravo AF: 0.000166

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000107 AC: 13

EpiCase AF: 0.000274

EpiControl AF: 0.000475

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	-	Neurodegeneration with brain iron accumulation (1)
1	-	-	Neurodegeneration with brain iron accumulation 7 (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.38
CADD	Pathogenic	26
DANN	Benign	0.96
DEOGEN2	Benign	0.044	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.053	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		8.0
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.73	N
REVEL	Benign	0.098
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.043	D
Polyphen		0.058	B
Vest4		0.32
MVP		0.068
MPC		0.35
ClinPred		0.10	T
GERP RS		4.7
Varity_R		0.26
gMVP		0.60
Mutation Taster		=2/98	disease causing (ClinVar)

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: rs201191394; hg19: chr6-139266774;