X-70281705-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_004312.3(ARR3):c.1106C>T(p.Thr369Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,073,644 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000011 (0 hom. 4 hem.)
• Consequence: ARR3 NM_004312.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.04

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]

PDZD11 (HGNC:28034): (PDZ domain containing 11) Enables protein C-terminus binding activity. Involved in pore complex assembly. Located in basolateral plasma membrane and cytosol. Part of pore complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08534536).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARR3	NM_004312.3	c.1106C>T	p.Thr369Met	missense_variant	17/17	ENST00000307959.9
ARR3	XM_047442105.1	c.1130C>T	p.Thr377Met	missense_variant	16/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARR3	ENST00000307959.9	c.1106C>T	p.Thr369Met	missense_variant	17/17	1	NM_004312.3	P1
PDZD11	ENST00000695560.1	c.*667G>A		3_prime_UTR_variant, NMD_transcript_variant	8/8

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.00000713 AC: 1 AN: 140181 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 43465

Gnomad AFR exome AF: 0.000102

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000112 AC: 12 AN: 1073644 Hom.: 0 Cov.: 30 AF XY: 0.0000114 AC XY: 4 AN XY: 349548

Gnomad4 AFR exome AF: 0.0000387

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000121

Gnomad4 OTH exome AF: 0.0000221

GnomAD4 genome Cov.: 23

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.00000853 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 26, 2022

The c.1106C>T (p.T369M) alteration is located in exon 17 (coding exon 16) of the ARR3 gene. This alteration results from a C to T substitution at nucleotide position 1106, causing the threonine (T) at amino acid position 369 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.96
Cadd	Benign	5.0
Dann	Benign	0.95
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.74	T;T
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.085	T;T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.24	T
Sift4G	Uncertain	0.021	D;D
Polyphen		0.047	.;B
Vest4		0.10
MVP		0.36
MPC		0.077
ClinPred		0.049	T
GERP RS		0.18
Varity_R		0.023
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs369964106; hg19: chrX-69501555; COSMIC: COSV99333608; COSMIC: COSV99333608;