6-138905135-GA-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_001286611.2(REPS1):c.2323-4del variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00324 in 1,597,242 control chromosomes in the GnomAD database, including 18 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (17 hom.)
• Consequence: REPS1 NM_001286611.2 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.234

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP6: Variant 6-138905135-GA-G is Benign according to our data. Variant chr6-138905135-GA-G is described in ClinVar as [Likely_benign]. Clinvar id is 1599842.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-138905135-GA-G is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
REPS1	NM_001286611.2	c.2323-4del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000450536.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
REPS1	ENST00000450536.7	c.2323-4del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001286611.2	P4

Frequencies

GnomAD3 genomes AF: 0.00222 AC: 338 AN: 152116 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00517

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00363

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00291 AC: 728 AN: 250520 Hom.: 1 AF XY: 0.00309 AC XY: 418 AN XY: 135418

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00122

Gnomad ASJ exome AF: 0.00457

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00473

Gnomad FIN exome AF: 0.00245

Gnomad NFE exome AF: 0.00371

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.00334 AC: 4830 AN: 1445008 Hom.: 17 Cov.: 25 AF XY: 0.00341 AC XY: 2456 AN XY: 719888

Gnomad4 AFR exome AF: 0.000514

Gnomad4 AMR exome AF: 0.00112

Gnomad4 ASJ exome AF: 0.00431

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00455

Gnomad4 FIN exome AF: 0.00266

Gnomad4 NFE exome AF: 0.00356

Gnomad4 OTH exome AF: 0.00313

GnomAD4 genome AF: 0.00222 AC: 338 AN: 152234 Hom.: 1 Cov.: 32 AF XY: 0.00189 AC XY: 141 AN XY: 74440

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00559

Gnomad4 FIN AF: 0.00160

Gnomad4 NFE AF: 0.00363

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00262 Hom.: 1

Bravo AF: 0.00201

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00421

EpiControl AF: 0.00386

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	REPS1: BP4 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 11, 2023	- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs554661735; hg19: chr6-139226272;