NM_001286611.2:c.2149G>A

Variant names:

• chr6-138908735-C-T
• rs1044418
• NM_001286611.2:c.2149G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001286611.2(REPS1):​c.2149G>A​(p.Val717Ile) variant causes a missense change. The variant allele was found at a frequency of 0.151 in 1,613,634 control chromosomes in the GnomAD database, including 19,850 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.15 (1763 hom., cov: 32)
  • Exomes 𝑓: 0.15 (18087 hom.)
• Consequence: REPS1 NM_001286611.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.33
• Publications: 33 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013096929).
• BP6: Variant 6-138908735-C-T is Benign according to our data. Variant chr6-138908735-C-T is described in ClinVar as Benign. ClinVar VariationId is 1164210.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.171 is higher than 0.05.

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.2149G>A	p.Val717Ile	missense	Exon 18 of 20	NP_001273540.1	Q96D71-1
	REPS1	NM_031922.5		c.2146G>A	p.Val716Ile	missense	Exon 18 of 20	NP_114128.3
	REPS1	NM_001128617.3		c.2068G>A	p.Val690Ile	missense	Exon 17 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.2149G>A	p.Val717Ile	missense	Exon 18 of 20	ENSP00000392065.2	Q96D71-1
	REPS1	ENST00000258062.9	TSL:1	c.2146G>A	p.Val716Ile	missense	Exon 18 of 20	ENSP00000258062.5	Q96D71-3
	REPS1	ENST00000409812.6	TSL:1	c.1876G>A	p.Val626Ile	missense	Exon 15 of 17	ENSP00000386699.2	Q96D71-2

Frequencies

GnomAD3 genomes AF: 0.148 AC: 22545 AN: 152048 Hom.: 1766 Cov.: 32

Gnomad AFR AF: 0.175

Gnomad AMI AF: 0.0625

Gnomad AMR AF: 0.0978

Gnomad ASJ AF: 0.0700

Gnomad EAS AF: 0.0316

Gnomad SAS AF: 0.0541

Gnomad FIN AF: 0.162

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.163

Gnomad OTH AF: 0.126

GnomAD2 exomes AF: 0.123 AC: 30834 AN: 251446 AF XY: 0.120

Gnomad AFR exome AF: 0.174

Gnomad AMR exome AF: 0.0662

Gnomad ASJ exome AF: 0.0673

Gnomad EAS exome AF: 0.0306

Gnomad FIN exome AF: 0.161

Gnomad NFE exome AF: 0.164

Gnomad OTH exome AF: 0.119

GnomAD4 exome AF: 0.151 AC: 221361 AN: 1461468 Hom.: 18087 Cov.: 32 AF XY: 0.148 AC XY: 107554 AN XY: 727046

African (AFR) AF: 0.171 AC: 5721 AN: 33468

American (AMR) AF: 0.0694 AC: 3105 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0693 AC: 1810 AN: 26130

East Asian (EAS) AF: 0.0334 AC: 1327 AN: 39688

South Asian (SAS) AF: 0.0511 AC: 4410 AN: 86248

European-Finnish (FIN) AF: 0.161 AC: 8579 AN: 53420

Middle Eastern (MID) AF: 0.0853 AC: 492 AN: 5766

European-Non Finnish (NFE) AF: 0.169 AC: 187611 AN: 1111652

Other (OTH) AF: 0.138 AC: 8306 AN: 60382

GnomAD4 genome AF: 0.148 AC: 22539 AN: 152166 Hom.: 1763 Cov.: 32 AF XY: 0.145 AC XY: 10785 AN XY: 74378

African (AFR) AF: 0.174 AC: 7244 AN: 41514

American (AMR) AF: 0.0978 AC: 1495 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0700 AC: 243 AN: 3470

East Asian (EAS) AF: 0.0316 AC: 164 AN: 5184

South Asian (SAS) AF: 0.0531 AC: 256 AN: 4824

European-Finnish (FIN) AF: 0.162 AC: 1715 AN: 10562

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.163 AC: 11067 AN: 68000

Other (OTH) AF: 0.125 AC: 263 AN: 2112

Alfa AF: 0.151 Hom.: 5493

Bravo AF: 0.145

TwinsUK AF: 0.172 AC: 636

ALSPAC AF: 0.174 AC: 672

ESP6500AA AF: 0.176 AC: 777

ESP6500EA AF: 0.162 AC: 1395

ExAC AF: 0.127 AC: 15398

Asia WGS AF: 0.0590 AC: 204 AN: 3478

EpiCase AF: 0.154

EpiControl AF: 0.150

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0087	T
Eigen	Benign	0.025
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
PhyloP100		4.3
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.055
Sift	Benign	0.15	T
Sift4G	Benign	0.18	T
Polyphen		0.0	B
Vest4		0.057
MPC		0.20
ClinPred		0.016	T
GERP RS		5.3
PromoterAI		-0.026	Neutral
Varity_R		0.055
gMVP		0.048
Mutation Taster		=97/3	polymorphism (auto)

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: rs1044418; hg19: chr6-139229872; COSMIC: COSV57810925; COSMIC: COSV57810925;