chr6-138905135-GA-G

Variant names:

• chr6-138905135-GA-G
• rs554661735
• NM_001286611.2:c.2323-4delT

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_001286611.2(REPS1):​c.2323-4delT variant causes a splice region, 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, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.234
• 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: Benign. The variant received -12 ACMG points.

• BP6: Variant 6-138905135-GA-G is Benign according to our data. Variant chr6-138905135-GA-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1599842.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 17 Unknown gene

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.2323-4delT		splice_region intron	N/A	NP_001273540.1	Q96D71-1
	REPS1	NM_031922.5		c.2320-4delT		splice_region intron	N/A	NP_114128.3
	REPS1	NM_001128617.3		c.2242-4delT		splice_region intron	N/A	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.2323-4delT		splice_region intron	N/A	ENSP00000392065.2	Q96D71-1
	REPS1	ENST00000258062.9	TSL:1	c.2320-4delT		splice_region intron	N/A	ENSP00000258062.5	Q96D71-3
	REPS1	ENST00000409812.6	TSL:1	c.2050-4delT		splice_region intron	N/A	ENSP00000386699.2	Q96D71-2

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

GnomAD2 exomes AF: 0.00291 AC: 728 AN: 250520 AF XY: 0.00309

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 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

African (AFR) AF: 0.000514 AC: 17 AN: 33100

American (AMR) AF: 0.00112 AC: 50 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.00431 AC: 112 AN: 25998

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39562

South Asian (SAS) AF: 0.00455 AC: 390 AN: 85784

European-Finnish (FIN) AF: 0.00266 AC: 142 AN: 53378

Middle Eastern (MID) AF: 0.00402 AC: 23 AN: 5728

European-Non Finnish (NFE) AF: 0.00356 AC: 3908 AN: 1096978

Other (OTH) AF: 0.00313 AC: 187 AN: 59834

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

African (AFR) AF: 0.000433 AC: 18 AN: 41550

American (AMR) AF: 0.000654 AC: 10 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00559 AC: 27 AN: 4830

European-Finnish (FIN) AF: 0.00160 AC: 17 AN: 10596

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00363 AC: 247 AN: 67998

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.23
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs554661735; hg19: chr6-139226272;