19-8697564-C-G

Variant names:

• chr19-8697564-C-G
• NM_178525.5:c.1138G>C
• ACTL9 p.Val380Leu

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PS1 PM2 PP3_Strong

The NM_178525.5(ACTL9):​c.1138G>C​(p.Val380Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ACTL9 NM_178525.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.42
• Publications: 0 publications found

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]

ACTL9 Gene-Disease associations (from GenCC):

• spermatogenic failure 53

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• non-syndromic male infertility due to sperm motility disorder

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PS1: Transcript NM_178525.5 (ACTL9) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.967

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178525.5. 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
	ACTL9	NM_178525.5	MANE Select	c.1138G>C	p.Val380Leu	missense	Exon 1 of 1	NP_848620.3	Q8TC94

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTL9	ENST00000324436.5	TSL:6 MANE Select	c.1138G>C	p.Val380Leu	missense	Exon 1 of 1	ENSP00000316674.3	Q8TC94

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.0	D
PhyloP100		7.4
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-2.4	N
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
gMVP		0.62
Mutation Taster		=32/68	disease causing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr19-8807914;