chrX-70276175-T-C

Variant names:

• chrX-70276175-T-C
• rs1555941116
• NM_004312.3:c.239T>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_004312.3(ARR3):​c.239T>C​(p.Leu80Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 22)
• Consequence: ARR3 NM_004312.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.645
• Publications: 4 publications found

Genes affected

ARR3 (HGNC:710): (arrestin 3) The protein encoded by this gene is a non-visual arrestin which binds to agonist-activated, phosphorylated G protein-coupled receptors. This binding uncouples the receptor from the heterotrimeric G protein, resulting in termination of the G protein-coupled receptor signaling. The encoded protein also is a part of the centrosome, interacting with gamma-tubulin to help regulate proper centrosome function. [provided by RefSeq, May 2016]

ARR3 Gene-Disease associations (from GenCC):

• myopia 26, X-linked, female-limited

  Inheritance: XL Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-70276175-T-C is Pathogenic according to our data. Variant chrX-70276175-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 478826.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.20372704). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004312.3. 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
	ARR3	NM_004312.3	MANE Select	c.239T>C	p.Leu80Pro	missense	Exon 6 of 17	NP_004303.2	P36575-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARR3	ENST00000307959.9	TSL:1 MANE Select	c.239T>C	p.Leu80Pro	missense	Exon 6 of 17	ENSP00000311538.8	P36575-1
	ARR3	ENST00000374495.7	TSL:1	c.239T>C	p.Leu80Pro	missense	Exon 6 of 16	ENSP00000363619.3	P36575-2
	ARR3	ENST00000480877.6	TSL:5	c.86T>C	p.Leu29Pro	missense	Exon 6 of 8	ENSP00000425505.1	D6RCT3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Myopia 26, X-linked, female-limited (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	12
DANN	Benign	0.81
DEOGEN2	Benign	0.026	T
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.65
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.076
Sift	Benign	0.35	T
Sift4G	Benign	0.30	T
Polyphen		0.65	P
Vest4		0.44
MutPred		0.41		Gain of disorder (P = 0.0154)
MVP		0.38
MPC		0.20
ClinPred		0.52	D
GERP RS		-3.3
Varity_R		0.62
gMVP		0.91
Mutation Taster		=8/92	disease causing (ClinVar)

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: rs1555941116; hg19: chrX-69496025;