5-57481597-C-A

Variant names:

• chr5-57481597-C-A
• rs562161532
• NM_001017992.4:c.1111G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001017992.4(ACTBL2):​c.1111G>T​(p.Val371Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,198 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V371I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ACTBL2 NM_001017992.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.96
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.924

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001017992.4. 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
	ACTBL2	NM_001017992.4	MANE Select	c.1111G>T	p.Val371Phe	missense	Exon 1 of 1	NP_001017992.1	Q562R1
	RMEL3	NR_186596.1		n.73-12478C>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTBL2	ENST00000423391.3	TSL:6 MANE Select	c.1111G>T	p.Val371Phe	missense	Exon 1 of 1	ENSP00000416706.1	Q562R1
	RMEL3	ENST00000506106.1	TSL:2	n.120-12478C>A		intron	N/A
	RMEL3	ENST00000771489.1		n.274-7057C>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250366 AF XY: 0.00000739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460198 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726342

African (AFR) AF: 0.00 AC: 0 AN: 33436

American (AMR) AF: 0.0000224 AC: 1 AN: 44618

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26052

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86098

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5132

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111502

Other (OTH) AF: 0.00 AC: 0 AN: 60272

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.52
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.56	D
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		5.0
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	-2.1	N
REVEL	Pathogenic	0.87
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.91
MutPred		0.80		Gain of glycosylation at P368 (P = 0.1454)
MVP		0.73
MPC		0.46
ClinPred		0.94	D
GERP RS		4.1
Varity_R		0.68
gMVP		0.39
Mutation Taster		=92/8	polymorphism

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: rs562161532; hg19: chr5-56777424;