9-108854859-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PP3_StrongBS2

The NM_006686.4(ACTL7B):​c.1072G>A​(p.Glu358Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000769 in 1,560,752 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: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000057 ( 0 hom. )

Consequence

ACTL7B
NM_006686.4 missense

Scores

12
6
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.88
Variant links:
Genes affected
ACTL7B (HGNC:162): (actin like 7B) The protein encoded by this gene is a member of a family of actin-related proteins (ARPs) which share significant amino acid sequence identity to conventional actins. Both actins and ARPs have an actin fold, which is an ATP-binding cleft, as a common feature. The ARPs are involved in diverse cellular processes, including vesicular transport, spindle orientation, nuclear migration and chromatin remodeling. This gene (ACTL7B), and related gene, ACTL7A, are intronless, and are located approximately 4 kb apart in a head-to-head orientation within the familial dysautonomia candidate region on 9q31. Based on mutational analysis of the ACTL7B gene in patients with this disorder, it was concluded that it is unlikely to be involved in the pathogenesis of dysautonomia. Unlike ACTL7A, the ACTL7B gene is expressed predominantly in the testis, however, its exact function is not known. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.972
BS2
High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ACTL7BNM_006686.4 linkc.1072G>A p.Glu358Lys missense_variant Exon 1 of 1 ENST00000374667.5 NP_006677.1 Q9Y614A0A140VKC6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ACTL7BENST00000374667.5 linkc.1072G>A p.Glu358Lys missense_variant Exon 1 of 1 6 NM_006686.4 ENSP00000363799.3 Q9Y614

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152218
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:
0.000771
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000332
AC:
7
AN:
210738
Hom.:
0
AF XY:
0.0000440
AC XY:
5
AN XY:
113592
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000420
Gnomad SAS 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:
0.00000568
AC:
8
AN:
1408534
Hom.:
0
Cov.:
31
AF XY:
0.0000101
AC XY:
7
AN XY:
695086
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000205
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152218
Hom.:
0
Cov.:
33
AF XY:
0.0000403
AC XY:
3
AN XY:
74368
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000771
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
ExAC
AF:
0.0000247
AC:
3

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Dec 11, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1072G>A (p.E358K) alteration is located in exon 1 (coding exon 1) of the ACTL7B gene. This alteration results from a G to A substitution at nucleotide position 1072, causing the glutamic acid (E) at amino acid position 358 to be replaced by a lysine (K). 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
Uncertain
0.53
BayesDel_addAF
Pathogenic
0.29
D
BayesDel_noAF
Pathogenic
0.51
CADD
Pathogenic
29
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.81
D
Eigen
Pathogenic
0.93
Eigen_PC
Pathogenic
0.83
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.86
D
M_CAP
Uncertain
0.22
D
MetaRNN
Pathogenic
0.97
D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.7
H
PrimateAI
Uncertain
0.61
T
PROVEAN
Uncertain
-3.2
D
REVEL
Pathogenic
0.92
Sift
Pathogenic
0.0
D
Sift4G
Uncertain
0.010
D
Polyphen
1.0
D
Vest4
0.89
MutPred
0.95
Gain of ubiquitination at E358 (P = 0.0452);
MVP
0.99
MPC
1.3
ClinPred
0.97
D
GERP RS
4.7
Varity_R
0.81
gMVP
0.88

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.

Other links and lift over

dbSNP: rs752064414; hg19: chr9-111617139; API