19-8697562-TAC-CAA

Variant names:

• chr19-8697562-TAC-CAA
• NM_178525.5:c.1138_1140delGTAinsTTG
• ACTL9 p.Val380Leu

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PS1

The NM_178525.5(ACTL9):​c.1138_1140delGTAinsTTG​(p.Val380Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. 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: Uncertain_significance. The variant received 4 ACMG points.

• PS1: Transcript NM_178525.5 (ACTL9) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.

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.1138_1140delGTAinsTTG	p.Val380Leu	missense	N/A	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.1138_1140delGTAinsTTG	p.Val380Leu	missense	N/A	ENSP00000316674.3	Q8TC94

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.4

Splicing

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: chr19-8807912;