chr6-138947835-C-G

Position:

• chr6-138947835-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_001286611.2(REPS1):​c.232G>C​(p.Val78Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: REPS1 NM_001286611.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 3.61

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-138947835-C-G is Pathogenic according to our data. Variant chr6-138947835-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 503503.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.13547665). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
REPS1	NM_001286611.2	c.232G>C	p.Val78Leu	missense_variant	2/20	ENST00000450536.7	NP_001273540.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
REPS1	ENST00000450536.7	c.232G>C	p.Val78Leu	missense_variant	2/20	1	NM_001286611.2	ENSP00000392065	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Neurodegeneration with brain iron accumulation 7 Pathogenic:2

Pathogenic, no assertion criteria provided	research	Institut IMAGINE, Institut National de la Sante et de la Recherche Medicale	-	The two affected individuals are sisters with compound heterozygous mutations: c.232G>C ; p.Val78Leu and c.338C>A ; p.Ala113Glu. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 27, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.033	T;T;.;T;.;.;T
Eigen	Benign	-0.24
Eigen_PC	Benign	0.035
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D;D
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.14	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.11	N;.;N;.;N;N;.
MutationTaster	Benign	0.99	D;D;D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.91	N;.;N;N;N;N;N
REVEL	Benign	0.071
Sift	Benign	0.30	T;.;T;T;T;T;T
Sift4G	Benign	0.20	T;T;T;T;T;T;T
Polyphen		0.0	B;.;.;.;B;B;B
Vest4		0.24
MutPred		0.46		Loss of ubiquitination at K74 (P = 0.1453);Loss of ubiquitination at K74 (P = 0.1453);Loss of ubiquitination at K74 (P = 0.1453);.;Loss of ubiquitination at K74 (P = 0.1453);Loss of ubiquitination at K74 (P = 0.1453);Loss of ubiquitination at K74 (P = 0.1453);
MVP		0.17
MPC		0.24
ClinPred		0.83	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.50

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554292444; hg19: chr6-139268972;