rs73757391

Positions:

• chr5-57482386-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001017992.4(ACTBL2):​c.322G>A​(p.Glu108Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00451 in 1,614,024 control chromosomes in the GnomAD database, including 311 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.024 (170 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (141 hom.)
• Consequence: ACTBL2 NM_001017992.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.14

Genes affected

ACTBL2 (HGNC:17780): (actin beta like 2) Predicted to enable protein kinase binding activity. Predicted to be a structural constituent of postsynaptic actin cytoskeleton. Predicted to be involved in axonogenesis and cell motility. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

RMEL3 (HGNC:53975): (enriched in melanoma 3)

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009886682).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0796 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTBL2	NM_001017992.4	c.322G>A	p.Glu108Lys	missense_variant	1/1	ENST00000423391.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTBL2	ENST00000423391.3	c.322G>A	p.Glu108Lys	missense_variant	1/1		NM_001017992.4	P1
RMEL3	ENST00000506106.1	n.120-11689C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0238 AC: 3615 AN: 152056 Hom.: 170 Cov.: 32

Gnomad AFR AF: 0.0819

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.0153

GnomAD3 exomes AF: 0.00637 AC: 1599 AN: 251008 Hom.: 76 AF XY: 0.00490 AC XY: 665 AN XY: 135638

Gnomad AFR exome AF: 0.0838

Gnomad AMR exome AF: 0.00471

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000388

Gnomad OTH exome AF: 0.00327

GnomAD4 exome AF: 0.00251 AC: 3665 AN: 1461848 Hom.: 141 Cov.: 31 AF XY: 0.00218 AC XY: 1584 AN XY: 727214

Gnomad4 AFR exome AF: 0.0831

Gnomad4 AMR exome AF: 0.00512

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000255

Gnomad4 OTH exome AF: 0.00541

GnomAD4 genome AF: 0.0238 AC: 3621 AN: 152176 Hom.: 170 Cov.: 32 AF XY: 0.0224 AC XY: 1669 AN XY: 74412

Gnomad4 AFR AF: 0.0819

Gnomad4 AMR AF: 0.0111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.0152

Alfa AF: 0.00417 Hom.: 38

Bravo AF: 0.0268

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0772 AC: 340

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00779 AC: 946

Asia WGS AF: 0.00434 AC: 15 AN: 3474

EpiCase AF: 0.000273

EpiControl AF: 0.000119

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0099	T
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Pathogenic	4.5	H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.1	D
REVEL	Pathogenic	0.84
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.69
MVP		0.79
MPC		0.40
ClinPred		0.076	T
GERP RS		4.0
Varity_R		0.85
gMVP		0.90

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: rs73757391; hg19: chr5-56778213;