chr12-122981685-C-T

Position:

• chr12-122981685-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000315580.10(ARL6IP4):​c.275C>T​(p.Ser92Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000199 in 1,553,446 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: ARL6IP4 ENST00000315580.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.71

Genes affected

ARL6IP4 (HGNC:18076): (ADP ribosylation factor like GTPase 6 interacting protein 4) Enables identical protein binding activity. Predicted to be involved in RNA splicing and mRNA processing. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ABCB9 (HGNC:50): (ATP binding cassette subfamily B member 9) The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the MDR/TAP subfamily. Members of the MDR/TAP subfamily are involved in multidrug resistance as well as antigen presentation. This family member functions in the translocation of peptides from the cytosol into the lysosomal lumen. Alternative splicing of this gene results in distinct isoforms which are likely to have different substrate specificities. [provided by RefSeq, Jul 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27279437).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARL6IP4	NM_018694.4	c.275C>T	p.Ser92Phe	missense_variant	3/6	ENST00000315580.10	NP_061164.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARL6IP4	ENST00000315580.10	c.275C>T	p.Ser92Phe	missense_variant	3/6	1	NM_018694.4	ENSP00000313422	A1

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000157 AC: 25 AN: 159684 Hom.: 0 AF XY: 0.000178 AC XY: 15 AN XY: 84434

Gnomad AFR exome AF: 0.000108

Gnomad AMR exome AF: 0.000199

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000430

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000130

Gnomad OTH exome AF: 0.000218

GnomAD4 exome AF: 0.000201 AC: 281 AN: 1401318 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 130 AN XY: 691702

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000249

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000226

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000229

Gnomad4 OTH exome AF: 0.000120

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152128 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74314

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.000957

Alfa AF: 0.000121 Hom.: 0

Bravo AF: 0.000200

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000229 AC: 1

ESP6500EA AF: 0.000352 AC: 3

ExAC AF: 0.0000963 AC: 11

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 14, 2023

The c.644C>T (p.S215F) alteration is located in exon 3 (coding exon 3) of the ARL6IP4 gene. This alteration results from a C to T substitution at nucleotide position 644, causing the serine (S) at amino acid position 215 to be replaced by a phenylalanine (F). 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	0.30
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T;.;.;T;.;.;.;.;T;T;T;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.83	T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.27	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Uncertain	2.7	M;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.2	.;.;.;D;.;D;D;D;D;D;D;D
REVEL	Benign	0.28
Sift	Uncertain	0.0010	.;.;.;D;.;D;D;D;T;D;D;D
Sift4G	Uncertain	0.010	D;D;D;D;D;D;D;D;D;D;D;D
Vest4		0.32
MVP		0.80
MPC		0.0095
ClinPred		0.17	T
GERP RS		4.9
Varity_R		0.25
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs377049391; hg19: chr12-123466232;