9-108862402-C-T

Variant names:

• chr9-108862402-C-T
• NM_006687.4:c.80C>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006687.4(ACTL7A):​c.80C>T​(p.Ala27Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A27D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: ACTL7A NM_006687.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.848

Genes affected

ACTL7A (HGNC:161): (actin like 7A) The protein encoded by this gene is a member of a family of actin-related proteins (ARPs) which share significant amino acid sequence identity to conventional actins. Both actins and ARPs have an actin fold, which is an ATP-binding cleft, as a common feature. The ARPs are involved in diverse cellular processes, including vesicular transport, spindle orientation, nuclear migration and chromatin remodeling. This gene (ACTL7A), and related gene, ACTL7B, are intronless, and are located approximately 4 kb apart in a head-to-head orientation within the familial dysautonomia candidate region on 9q31. Based on mutational analysis of the ACTL7A gene in patients with this disorder, it was concluded that it is unlikely to be involved in the pathogenesis of dysautonomia. The ACTL7A gene is expressed in a wide variety of adult tissues, however, its exact function is not known. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04055214).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTL7A	NM_006687.4	c.80C>T	p.Ala27Val	missense_variant	Exon 1 of 1	ENST00000333999.5	NP_006678.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTL7A	ENST00000333999.5	c.80C>T	p.Ala27Val	missense_variant	Exon 1 of 1	6	NM_006687.4	ENSP00000334300.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461770 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727184

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	0.93
DANN	Benign	0.89
DEOGEN2	Benign	0.013	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.041	T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	0.0	N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.29
Sift	Benign	0.61	T
Sift4G	Benign	0.19	T
Polyphen		0.0	B
Vest4		0.077
MutPred		0.33		Gain of sheet (P = 0.0016);
MVP		0.55
MPC		0.077
ClinPred		0.035	T
GERP RS		-3.1
Varity_R		0.028
gMVP		0.14

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: chr9-111624682; COSMIC: COSV61776289;