chr5-57481938-C-A

Position:

• chr5-57481938-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 6P and 4B. PM2 PP3_Strong BS2

The NM_001017992.4(ACTBL2):​c.770G>T​(p.Arg257Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: ACTBL2 NM_001017992.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.04

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTBL2	NM_001017992.4	c.770G>T	p.Arg257Leu	missense_variant	1/1	ENST00000423391.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTBL2	ENST00000423391.3	c.770G>T	p.Arg257Leu	missense_variant	1/1		NM_001017992.4	P1
RMEL3	ENST00000506106.1	n.120-12137C>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461834 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727210

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Mar 16, 2024

The c.770G>T (p.R257L) alteration is located in exon 1 (coding exon 1) of the ACTBL2 gene. This alteration results from a G to T substitution at nucleotide position 770, causing the arginine (R) at amino acid position 257 to be replaced by a leucine (L). 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	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Uncertain	2.9	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Pathogenic	0.89
Sift4G	Uncertain	0.014	D
Polyphen		0.95	P
Vest4		0.66
MutPred		0.95		Gain of catalytic residue at A261 (P = 0.1821);
MVP		0.64
MPC		0.31
ClinPred		0.99	D
GERP RS		4.0
Varity_R		0.86
gMVP		0.50

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-56777765;