chr6-138908719-T-G

Variant names:

• chr6-138908719-T-G
• NM_001286611.2:c.2165A>C

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.2165A>C​(p.Gln722Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,862 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: REPS1 NM_001286611.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.51
• 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=0.21543583).

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.2165A>C	p.Gln722Pro	missense	Exon 18 of 20	NP_001273540.1	Q96D71-1
	REPS1	NM_031922.5		c.2162A>C	p.Gln721Pro	missense	Exon 18 of 20	NP_114128.3
	REPS1	NM_001128617.3		c.2084A>C	p.Gln695Pro	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.2165A>C	p.Gln722Pro	missense	Exon 18 of 20	ENSP00000392065.2	Q96D71-1
	REPS1	ENST00000258062.9	TSL:1	c.2162A>C	p.Gln721Pro	missense	Exon 18 of 20	ENSP00000258062.5	Q96D71-3
	REPS1	ENST00000409812.6	TSL:1	c.1892A>C	p.Gln631Pro	missense	Exon 15 of 17	ENSP00000386699.2	Q96D71-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461862 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727234

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111984

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

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	0.065
BayesDel_addAF	Benign	-0.061	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.0086	T
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.97	L
PhyloP100		5.5
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	0.31	N
REVEL	Benign	0.19
Sift	Benign	0.18	T
Sift4G	Benign	0.99	T
Polyphen		1.0	D
Vest4		0.50
MutPred		0.11		Loss of solvent accessibility (P = 0.045)
MVP		0.22
MPC		0.30
ClinPred		0.67	D
GERP RS		2.9
PromoterAI		0.022	Neutral
Varity_R		0.13
gMVP		0.29
Mutation Taster		=67/33	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

hg19: chr6-139229856;