Genetic Variant NM_001024675.2:c.340G>A (chr20-33667837-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001024675.2(ACTL10):c.340G>A(p.Val114Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000677 in 1,610,814 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

ACTL10
NM_001024675.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.16

Publications

0 publications found

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]

ACTL10 links:

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]

NECAB3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005910456).

BS2

High AC in GnomAd4 at 56 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001024675.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ACTL10	NM_001024675.2	MANE Select	c.340G>A	p.Val114Ile	missense	Exon 1 of 1	NP_001019846.1	Q5JWF8
NECAB3	NM_031232.4	MANE Select	c.387+1538C>T		intron	N/A	NP_112509.3
NECAB3	NM_031231.4		c.387+1538C>T		intron	N/A	NP_112508.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ACTL10	ENST00000677665.1	MANE Select	c.340G>A	p.Val114Ile	missense	Exon 1 of 1	ENSP00000504425.1	Q5JWF8
NECAB3	ENST00000246190.11	TSL:5 MANE Select	c.387+1538C>T		intron	N/A	ENSP00000246190.6	Q96P71-1
NECAB3	ENST00000375238.8	TSL:1	c.387+1538C>T		intron	N/A	ENSP00000364386.4	Q96P71-2

Frequencies

GnomAD3 genomes

AF:

0.000368

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00118

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.00

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.0000921

AC:

AN:

238984

AF XY:

0.0000458

show subpopulations

Gnomad AFR exome

AF:

0.00114

Gnomad AMR exome

AF:

0.000118

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:

0.000172

GnomAD4 exome

AF:

0.0000363

AC:

AN:

1458556

Hom.:

Cov.:

AF XY:

0.0000221

AC XY:

AN XY:

725442

show subpopulations

African (AFR)

AF:

0.00123

AC:

AN:

33436

American (AMR)

AF:

0.0000673

AC:

AN:

44576

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26046

East Asian (EAS)

AF:

0.00

AC:

AN:

39620

South Asian (SAS)

AF:

0.00

AC:

AN:

86062

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51800

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111042

Other (OTH)

AF:

0.000116

AC:

AN:

60234

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000368

AC:

AN:

152258

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.00118

AC:

AN:

41564

American (AMR)

AF:

0.000262

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68016

Other (OTH)

AF:

0.00142

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000263

Hom.:

Bravo

AF:

0.000468

ESP6500AA

AF:

0.000910

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000116

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.63

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.28

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.39

M_CAP

Benign

0.0075

MetaRNN

Benign

0.0059

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-0.65

PhyloP100

1.2

PrimateAI

Benign

0.38

PROVEAN

Benign

0.37

REVEL

Benign

0.064

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0030

Vest4

0.025

MVP

0.11

MPC

0.28

ClinPred

0.021

GERP RS

-1.1

Varity_R

0.024

gMVP

0.14

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over