20-33667709-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_001024675.2(ACTL10):​c.212C>T​(p.Ala71Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,611,964 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

ACTL10
NM_001024675.2 missense

Scores

2
6
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.01
Variant links:
Genes affected
ACTL10 (HGNC:16127): (actin like 10) Predicted to be part of dynactin complex. [provided by Alliance of Genome Resources, Apr 2022]
NECAB3 (HGNC:15851): (N-terminal EF-hand calcium binding protein 3) The protein encoded by this gene interacts with the amino-terminal domain of the neuron-specific X11-like protein (X11L), inhibits the association of X11L with amyloid precursor protein through a non-competitive mechanism, and abolishes the suppression of beta-amyloid production by X11L. This protein, together with X11L, may play an important role in the regulatory system of amyloid precursor protein metabolism and beta-amyloid generation. The protein is phosphorylated by NIMA-related expressed kinase 2, and localizes to the Golgi apparatus. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.2853882).
BS2
High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ACTL10NM_001024675.2 linkc.212C>T p.Ala71Val missense_variant Exon 1 of 1 ENST00000677665.1 NP_001019846.1 Q5JWF8
NECAB3NM_031232.4 linkc.387+1666G>A intron_variant Intron 5 of 11 ENST00000246190.11 NP_112509.3 Q96P71-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ACTL10ENST00000677665.1 linkc.212C>T p.Ala71Val missense_variant Exon 1 of 1 NM_001024675.2 ENSP00000504425.1 Q5JWF8
NECAB3ENST00000246190.11 linkc.387+1666G>A intron_variant Intron 5 of 11 5 NM_031232.4 ENSP00000246190.6 Q96P71-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152224
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000343
AC:
5
AN:
1459740
Hom.:
0
Cov.:
32
AF XY:
0.00000275
AC XY:
2
AN XY:
726240
show subpopulations
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:
0.00000360
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152224
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74360
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Sep 30, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.212C>T (p.A71V) alteration is located in exon 1 (coding exon 1) of the ACTL10 gene. This alteration results from a C to T substitution at nucleotide position 212, causing the alanine (A) at amino acid position 71 to be replaced by a valine (V). 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
0.10
BayesDel_addAF
Benign
-0.036
T
BayesDel_noAF
Benign
-0.29
CADD
Benign
17
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.62
D
Eigen
Benign
-0.68
Eigen_PC
Benign
-0.82
FATHMM_MKL
Benign
0.23
N
LIST_S2
Benign
0.54
T
M_CAP
Pathogenic
0.36
D
MetaRNN
Benign
0.29
T
MetaSVM
Uncertain
0.28
D
MutationAssessor
Benign
1.9
L
PrimateAI
Benign
0.33
T
PROVEAN
Uncertain
-3.0
D
REVEL
Uncertain
0.40
Sift
Pathogenic
0.0
D
Sift4G
Uncertain
0.018
D
Polyphen
0.084
B
Vest4
0.074
MutPred
0.65
Gain of methylation at K75 (P = 0.0768);
MVP
0.32
MPC
0.55
ClinPred
0.83
D
GERP RS
0.39
RBP_binding_hub_radar
1.1
RBP_regulation_power_radar
2.9
Varity_R
0.47
gMVP
0.41

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs759248853; hg19: chr20-32255515; COSMIC: COSV99864776; COSMIC: COSV99864776; API