NM_001661.4:c.26C>T

Variant names:

• chr17-43399758-C-T
• rs1854203889
• NM_001661.4:c.26C>T

Variant summary

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

The NM_001661.4(ARL4D):​c.26C>T​(p.Ala9Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000548 in 1,461,138 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: ARL4D NM_001661.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.07
• Publications: 0 publications found

Genes affected

ARL4D (HGNC:656): (ADP ribosylation factor like GTPase 4D) ADP-ribosylation factor 4D is a member of the ADP-ribosylation factor family of GTP-binding proteins. ARL4D is closely similar to ARL4A and ARL4C and each has a nuclear localization signal and an unusually high guanine nucleotide exchange rate. This protein may play a role in membrane-associated intracellular trafficking. [provided by RefSeq, Jul 2021]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37573165).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001661.4. 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
	ARL4D	NM_001661.4	MANE Select	c.26C>T	p.Ala9Val	missense	Exon 2 of 2	NP_001652.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARL4D	ENST00000320033.5	TSL:1 MANE Select	c.26C>T	p.Ala9Val	missense	Exon 2 of 2	ENSP00000322628.2	P49703
	ARL4D	ENST00000869170.1		c.26C>T	p.Ala9Val	missense	Exon 2 of 2	ENSP00000539229.1
	ARL4D	ENST00000869171.1		c.26C>T	p.Ala9Val	missense	Exon 2 of 2	ENSP00000539230.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1461138 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726804

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26082

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86216

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000720 AC: 8 AN: 1111444

Other (OTH) AF: 0.00 AC: 0 AN: 60366

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.048	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.099	T
Eigen	Benign	0.18
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	1.6	L
PhyloP100		4.1
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.86	N
REVEL	Benign	0.28
Sift	Benign	0.12	T
Sift4G	Benign	0.48	T
Polyphen		0.89	P
Vest4		0.45
MutPred		0.50		Loss of disorder (P = 0.0508)
MVP		0.79
MPC		1.5
ClinPred		0.82	D
GERP RS		4.8
Varity_R		0.22
gMVP		0.62
Mutation Taster		=60/40	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1854203889; hg19: chr17-41477126; COSMIC: COSV60721725; COSMIC: COSV60721725;