9-124862400-A-T

Variant names:

• chr9-124862400-A-T
• rs10986468
• NM_030978.3:c.-984+2A>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 4P and 8B. PVS1_Strong BA1

The NM_030978.3(ARPC5L):​c.-984+2A>T variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.34 in 155,750 control chromosomes in the GnomAD database, including 9,760 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.34 (9463 hom., cov: 31)
  • Exomes 𝑓: 0.35 (297 hom.)
• Consequence: ARPC5L NM_030978.3 splice_donor, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0330
• Publications: 5 publications found

Genes affected

ARPC5L (HGNC:23366): (actin related protein 2/3 complex subunit 5 like) Predicted to enable actin filament binding activity. Predicted to be involved in Arp2/3 complex-mediated actin nucleation and cell migration. Located in extracellular exosome and focal adhesion. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.5822511 fraction of the gene. Cryptic splice site detected, with MaxEntScore 7.6, offset of 0 (no position change), new splice context is: gagGTattt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.419 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030978.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARPC5L	NM_030978.3	MANE Select	c.-984+2A>T		splice_donor intron	N/A	NP_112240.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARPC5L	ENST00000353214.6	TSL:2 MANE Select	c.-984+2A>T		splice_donor intron	N/A	ENSP00000345361.2

Frequencies

GnomAD3 genomes AF: 0.340 AC: 51565 AN: 151580 Hom.: 9464 Cov.: 31

Gnomad AFR AF: 0.223

Gnomad AMI AF: 0.365

Gnomad AMR AF: 0.327

Gnomad ASJ AF: 0.391

Gnomad EAS AF: 0.362

Gnomad SAS AF: 0.351

Gnomad FIN AF: 0.242

Gnomad MID AF: 0.459

Gnomad NFE AF: 0.423

Gnomad OTH AF: 0.344

GnomAD4 exome AF: 0.346 AC: 1404 AN: 4054 Hom.: 297 Cov.: 0 AF XY: 0.349 AC XY: 776 AN XY: 2226

African (AFR) AF: 0.181 AC: 33 AN: 182

American (AMR) AF: 0.246 AC: 29 AN: 118

Ashkenazi Jewish (ASJ) AF: 0.314 AC: 54 AN: 172

East Asian (EAS) AF: 0.287 AC: 43 AN: 150

South Asian (SAS) AF: 0.332 AC: 115 AN: 346

European-Finnish (FIN) AF: 0.192 AC: 30 AN: 156

Middle Eastern (MID) AF: 0.357 AC: 5 AN: 14

European-Non Finnish (NFE) AF: 0.374 AC: 993 AN: 2652

Other (OTH) AF: 0.386 AC: 102 AN: 264

GnomAD4 genome AF: 0.340 AC: 51573 AN: 151696 Hom.: 9463 Cov.: 31 AF XY: 0.331 AC XY: 24549 AN XY: 74120

African (AFR) AF: 0.223 AC: 9216 AN: 41354

American (AMR) AF: 0.326 AC: 4970 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.391 AC: 1354 AN: 3466

East Asian (EAS) AF: 0.362 AC: 1863 AN: 5142

South Asian (SAS) AF: 0.351 AC: 1681 AN: 4792

European-Finnish (FIN) AF: 0.242 AC: 2537 AN: 10496

Middle Eastern (MID) AF: 0.452 AC: 133 AN: 294

European-Non Finnish (NFE) AF: 0.423 AC: 28751 AN: 67906

Other (OTH) AF: 0.350 AC: 736 AN: 2104

Alfa AF: 0.370 Hom.: 1328

Bravo AF: 0.343

Asia WGS AF: 0.351 AC: 1221 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	9.7
DANN	Benign	0.62
PhyloP100		-0.033
PromoterAI		0.082	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10986468; hg19: chr9-127624679;