rs863223352

Variant names:

• chr17-81683794-C-A
• rs863223352
• NM_001040025.3:c.-41G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PP5_Moderate BP4

The NM_001040025.3(ARL16):​c.-41G>T variant causes a 5 prime UTR 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. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ARL16 NM_001040025.3 5_prime_UTR
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.344
• Publications: 0 publications found

Genes affected

ARL16 (HGNC:27902): (ADP ribosylation factor like GTPase 16) The protein encoded by this gene belongs to the ARL (ADP-ribosylation factor-like) family of proteins, which are structurally related to ADP-ribosylation factors (ARFs). This protein has been shown to have an inhibitory role in the cellular antiviral response. This gene product interacts with the C-terminal domain of the DEXD/H-box helicase 58 (DDX58) gene product. This interaction was found to suppress the association between the DDX58 gene product and RNA, thereby negatively regulating the activity of the DDX58 gene product. [provided by RefSeq, Jul 2016]

HGS (HGNC:4897): (hepatocyte growth factor-regulated tyrosine kinase substrate) The protein encoded by this gene regulates endosomal sorting and plays a critical role in the recycling and degradation of membrane receptors. The encoded protein sorts monoubiquitinated membrane proteins into the multivesicular body, targeting these proteins for lysosome-dependent degradation. [provided by RefSeq, Dec 2010]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-81683794-C-A is Pathogenic according to our data. Variant chr17-81683794-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 208393.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.08498457). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001040025.3. 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
	ARL16	NM_001040025.3	MANE Select	c.-41G>T		5_prime_UTR	Exon 1 of 5	NP_001035114.2
	ARL16	NM_001329608.2		c.-708G>T		5_prime_UTR	Exon 1 of 5	NP_001316537.1
	ARL16	NR_138058.2		n.4G>T		non_coding_transcript_exon	Exon 1 of 6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARL16	ENST00000622299.5	TSL:1 MANE Select	c.-41G>T		5_prime_UTR	Exon 1 of 5	ENSP00000483183.1
	HGS	ENST00000677161.1		c.-165+166C>A		intron	N/A	ENSP00000503695.1
	HGS	ENST00000329138.9	TSL:1 MANE Select	c.-273C>A		upstream_gene	N/A	ENSP00000331201.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1452828 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 723096

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 86198

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45230

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111534

Other (OTH) AF: 0.00 AC: 0 AN: 60224

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Childhood-onset schizophrenia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	6.9
DANN	Benign	0.64
DEOGEN2	Benign	0.0037	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.085	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.34
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	0.21	N
REVEL	Benign	0.15
Sift	Benign	0.063	T
Sift4G	Benign	0.26	T
Polyphen		0.023	B
Vest4		0.090
MutPred		0.54		Loss of methylation at R11 (P = 0.0012)
MVP		0.39
MPC		0.075
ClinPred		0.57	D
GERP RS		-7.8
PromoterAI		-0.0017	Neutral
Varity_R		0.068
gMVP		0.37

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs863223352; hg19: chr17-79650824; COSMIC: COSV106472666; COSMIC: COSV106472666;