NM_001024675.2:c.158C>A

Variant names:

• chr20-33667655-C-A
• rs549272201
• NM_001024675.2:c.158C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001024675.2(ACTL10):​c.158C>A​(p.Ser53*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000686 in 1,457,590 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.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ACTL10 NM_001024675.2 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.10
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTL10	NM_001024675.2	MANE Select	c.158C>A	p.Ser53*	stop_gained	Exon 1 of 1	NP_001019846.1	Q5JWF8
	NECAB3	NM_031232.4	MANE Select	c.387+1720G>T		intron	N/A	NP_112509.3
	NECAB3	NM_031231.4		c.387+1720G>T		intron	N/A	NP_112508.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTL10	ENST00000677665.1	MANE Select	c.158C>A	p.Ser53*	stop_gained	Exon 1 of 1	ENSP00000504425.1	Q5JWF8
	NECAB3	ENST00000246190.11	TSL:5 MANE Select	c.387+1720G>T		intron	N/A	ENSP00000246190.6	Q96P71-1
	NECAB3	ENST00000375238.8	TSL:1	c.387+1720G>T		intron	N/A	ENSP00000364386.4	Q96P71-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457590 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 725078

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33390

American (AMR) AF: 0.00 AC: 0 AN: 44554

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26042

East Asian (EAS) AF: 0.00 AC: 0 AN: 39526

South Asian (SAS) AF: 0.00 AC: 0 AN: 85962

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51114

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111036

Other (OTH) AF: 0.00 AC: 0 AN: 60202

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.90	D
PhyloP100		4.1
Vest4		0.039
GERP RS		4.9
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.8
Mutation Taster		=131/69	polymorphism

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

Other links and lift over

dbSNP: rs549272201; hg19: chr20-32255461; COSMIC: COSV55777610; COSMIC: COSV55777610;