19-8697747-C-A

Variant names:

• chr19-8697747-C-A
• NM_178525.5:c.955G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_178525.5(ACTL9):​c.955G>T​(p.Ala319Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ACTL9 NM_178525.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.428
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15188447).

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.955G>T	p.Ala319Ser	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.955G>T	p.Ala319Ser	missense	Exon 1 of 1	ENSP00000316674.3	Q8TC94

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	18
DANN	Uncertain	0.99
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.84	D
M_CAP	Benign	0.0057	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.43
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.29	N
REVEL	Benign	0.058
Sift	Benign	0.039	D
Sift4G	Uncertain	0.019	D
Vest4		0.40
MutPred		0.53		Gain of disorder (P = 0.032)
MVP		0.36
MPC		0.68
ClinPred		0.32	T
GERP RS		2.2
gMVP		0.68
Mutation Taster		=96/4	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

hg19: chr19-8808097;