20-33667542-C-G

Position:

chr20-33667542-C-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_ModerateBP6_ModerateBS2

The NM_001024675.2(ACTL10):c.45C>G(p.Phe15Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000207 in 1,545,632 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

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

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

ACTL10
NM_001024675.2 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 3.25

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 made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0863657).

BP6

Variant 20-33667542-C-G is Benign according to our data. Variant chr20-33667542-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 2495534.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAdExome4 at 31 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTL10	NM_001024675.2 linkuse as main transcript	c.45C>G	p.Phe15Leu	missense_variant	1/1	ENST00000677665.1	NP_001019846.1
NECAB3	NM_031232.4 linkuse as main transcript	c.387+1833G>C		intron_variant		ENST00000246190.11	NP_112509.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTL10	ENST00000677665.1 linkuse as main transcript	c.45C>G	p.Phe15Leu	missense_variant	1/1		NM_001024675.2	ENSP00000504425	P1
NECAB3	ENST00000246190.11 linkuse as main transcript	c.387+1833G>C		intron_variant		5	NM_031232.4	ENSP00000246190		Q96P71-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152214

Hom.:

Cov.:

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

GnomAD3 exomes

AF:

0.0000590

AC:

AN:

152644

Hom.:

AF XY:

0.0000472

AC XY:

AN XY:

84718

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000147

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000222

AC:

AN:

1393418

Hom.:

Cov.:

AF XY:

0.0000160

AC XY:

AN XY:

686888

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000277

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000241

Gnomad4 OTH exome

AF:

0.0000694

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74372

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:

0.0000113

ExAC

AF:

0.0000957

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 13, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.71

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.28

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.31

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.44

M_CAP

Benign

0.010

MetaRNN

Benign

0.086

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-0.15

MutationTaster

Benign

0.98

D;D;N

PrimateAI

Benign

0.45

PROVEAN

Benign

0.31

REVEL

Benign

0.066

Sift

Benign

0.12

Sift4G

Benign

0.22

Polyphen

0.0

Vest4

0.015

MutPred

0.60

Loss of catalytic residue at F15 (P = 0.0173);

MVP

0.30

MPC

0.39

ClinPred

0.16

GERP RS

2.6

Varity_R

0.16

gMVP

0.36

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over