11-30336665-G-A

Position:

• chr11-30336665-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_152316.3(ARL14EP):​c.653G>A​(p.Gly218Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARL14EP NM_152316.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.94

Genes affected

ARL14EP (HGNC:26798): (ADP ribosylation factor like GTPase 14 effector protein) The protein encoded by this gene is an effector protein. It interacts with ADP-ribosylation factor-like 14 [ARL14, also known as ADP-ribosylation factor 7 (ARF7)], beta-actin (ACTB) and actin-based motor protein myosin 1E (MYO1E). ARL14 is a small GTPase; it controls the export of major histocompatibility class II molecules by connecting to the actin network via this effector protein. [provided by RefSeq, Sep 2014]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.882
• PP5: Variant 11-30336665-G-A is Pathogenic according to our data. Variant chr11-30336665-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 183284.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-30336665-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARL14EP	NM_152316.3	c.653G>A	p.Gly218Glu	missense_variant	4/4	ENST00000282032.4	NP_689529.1
ARL14EP	XM_005252792.5	c.317G>A	p.Gly106Glu	missense_variant	4/4		XP_005252849.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARL14EP	ENST00000282032.4	c.653G>A	p.Gly218Glu	missense_variant	4/4	1	NM_152316.3	ENSP00000282032	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Abnormal facial shape;C0557874:Global developmental delay;C4551560:Truncal obesity;C4551563:Microcephaly Pathogenic:1

Likely pathogenic, flagged submission

research

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Dec 01, 2014

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Pathogenic	3.4	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-7.3	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.62		Gain of helix (P = 0.0078);
MVP		0.91
MPC		1.1
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.99
gMVP		0.85

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: rs730882201; hg19: chr11-30358212;