19-8698009-G-T

Variant names:

• chr19-8698009-G-T
• NM_178525.5:c.693C>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_178525.5(ACTL9):​c.693C>A​(p.Phe231Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000276 in 1,451,838 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: not found (cov: 31)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: ACTL9 NM_178525.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.76

Genes affected

ACTL9 (HGNC:28494): (actin like 9) Predicted to be located in cytoplasm. Predicted to be part of dynactin complex. Implicated in spermatogenic failure 53. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.769

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTL9	NM_178525.5	c.693C>A	p.Phe231Leu	missense_variant	Exon 1 of 1	ENST00000324436.5	NP_848620.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTL9	ENST00000324436.5	c.693C>A	p.Phe231Leu	missense_variant	Exon 1 of 1	6	NM_178525.5	ENSP00000316674.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000276 AC: 4 AN: 1451838 Hom.: 0 Cov.: 31 AF XY: 0.00000277 AC XY: 2 AN XY: 722680

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: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.693C>A (p.F231L) alteration is located in exon 1 (coding exon 1) of the ACTL9 gene. This alteration results from a C to A substitution at nucleotide position 693, causing the phenylalanine (F) at amino acid position 231 to be replaced by a leucine (L). 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
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	20
DANN	Uncertain	1.0
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.77	D;D
MetaSVM	Uncertain	0.72	D
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-4.0	D;.
REVEL	Uncertain	0.63
Sift	Uncertain	0.0020	D;.
Sift4G	Uncertain	0.037	D;D
Vest4		0.33
MutPred		0.55		Loss of stability (P = 0.1694);Loss of stability (P = 0.1694);
MVP		0.88
MPC		1.3
ClinPred		0.98	D
GERP RS		3.5
gMVP		0.93

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-8808359;