chr19-8697879-C-T

Variant names:

• chr19-8697879-C-T
• rs1555753339
• NM_178525.5:c.823G>A

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.823G>A​(p.Glu275Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,104 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ACTL9 NM_178525.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.705
• 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=0.17751789).

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.823G>A	p.Glu275Lys	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.823G>A	p.Glu275Lys	missense	Exon 1 of 1	ENSP00000316674.3	Q8TC94

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000805 AC: 2 AN: 248552 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000179

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461104 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726882

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52722

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111948

Other (OTH) AF: 0.0000166 AC: 1 AN: 60384

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000468 Hom.: 0

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	0.085
BayesDel_addAF	Benign	-0.019	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	12
DANN	Uncertain	0.99
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.069	N
M_CAP	Uncertain	0.096	D
MetaRNN	Benign	0.18	T
MetaSVM	Uncertain	0.19	D
PhyloP100		0.70
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.79	N
REVEL	Benign	0.21
Sift	Benign	0.21	T
Sift4G	Benign	0.19	T
Vest4		0.13
MutPred		0.35		Gain of MoRF binding (P = 0.0134)
MVP		0.71
MPC		0.80
ClinPred		0.19	T
GERP RS		3.3
gMVP		0.79
Mutation Taster		=75/25	polymorphism

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

Other links and lift over

dbSNP: rs1555753339; hg19: chr19-8808229;