1-17825978-G-A

Variant names:

• chr1-17825978-G-A
• rs2053713319
• NM_030812.3:c.560G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_030812.3(ACTL8):​c.560G>A​(p.Ser187Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,457,164 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ACTL8 NM_030812.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.19

Genes affected

ACTL8 (HGNC:24018): (actin like 8) Involved in epithelial cell differentiation. Predicted to be located in cytoplasm. Predicted to be part of dynactin complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTL8	NM_030812.3	c.560G>A	p.Ser187Asn	missense_variant	Exon 3 of 3	ENST00000375406.2	NP_110439.2
ACTL8	XM_011542212.3	c.560G>A	p.Ser187Asn	missense_variant	Exon 3 of 3		XP_011540514.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTL8	ENST00000375406.2	c.560G>A	p.Ser187Asn	missense_variant	Exon 3 of 3	1	NM_030812.3	ENSP00000364555.1
ACTL8	ENST00000617065.1	c.560G>A	p.Ser187Asn	missense_variant	Exon 2 of 2	2		ENSP00000481590.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1457164 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 725132

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.560G>A (p.S187N) alteration is located in exon 1 (coding exon 1) of the ACTL8 gene. This alteration results from a G to A substitution at nucleotide position 560, causing the serine (S) at amino acid position 187 to be replaced by an asparagine (N). 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	0.14
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.56	D;D
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.59	.;T
M_CAP	Benign	0.011	T
MetaRNN	Uncertain	0.52	D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;L
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.99	N;.
REVEL	Benign	0.13
Sift	Uncertain	0.020	D;.
Sift4G	Benign	0.31	T;T
Polyphen		0.97	D;D
Vest4		0.14
MutPred		0.57		Loss of ubiquitination at K190 (P = 0.0806);Loss of ubiquitination at K190 (P = 0.0806);
MVP		0.47
MPC		0.46
ClinPred		0.49	T
GERP RS		3.1
Varity_R		0.20
gMVP		0.73

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

Other links and lift over

dbSNP: rs2053713319; hg19: chr1-18152473;