9-108854700-T-C

Variant names:

• chr9-108854700-T-C
• rs776306463
• NM_006686.4:c.1231A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Moderate BS2

The NM_006686.4(ACTL7B):​c.1231A>G​(p.Ile411Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000367 in 1,361,266 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000037 (0 hom.)
• Consequence: ACTL7B NM_006686.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.227
• Publications: 0 publications found

Genes affected

ACTL7B (HGNC:162): (actin like 7B) 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 (ACTL7B), and related gene, ACTL7A, 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 ACTL7B gene in patients with this disorder, it was concluded that it is unlikely to be involved in the pathogenesis of dysautonomia. Unlike ACTL7A, the ACTL7B gene is expressed predominantly in the testis, however, its exact function is not known. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09622827).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006686.4. 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
	ACTL7B	NM_006686.4	MANE Select	c.1231A>G	p.Ile411Val	missense	Exon 1 of 1	NP_006677.1	Q9Y614

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTL7B	ENST00000374667.5	TSL:6 MANE Select	c.1231A>G	p.Ile411Val	missense	Exon 1 of 1	ENSP00000363799.3	Q9Y614

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000165 AC: 3 AN: 181360 AF XY: 0.0000314

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: 0.0000114

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000367 AC: 5 AN: 1361266 Hom.: 0 Cov.: 31 AF XY: 0.00000601 AC XY: 4 AN XY: 666076

African (AFR) AF: 0.00 AC: 0 AN: 30490

American (AMR) AF: 0.00 AC: 0 AN: 30318

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20088

East Asian (EAS) AF: 0.00 AC: 0 AN: 38402

South Asian (SAS) AF: 0.0000572 AC: 4 AN: 69926

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49678

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4498

European-Non Finnish (NFE) AF: 9.42e-7 AC: 1 AN: 1061928

Other (OTH) AF: 0.00 AC: 0 AN: 55938

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000166 AC: 2

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	0.078
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	15
DANN	Benign	0.83
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.086
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.096	T
MetaSVM	Uncertain	-0.027	T
MutationAssessor	Benign	0.17	N
PhyloP100		0.23
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.19	N
REVEL	Uncertain	0.38
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.45	B
Vest4		0.036
MutPred		0.53		Loss of catalytic residue at I411 (P = 0.0297)
MVP		0.62
MPC		0.34
ClinPred		0.096	T
GERP RS		4.9
Varity_R		0.060
gMVP		0.098
Mutation Taster		=82/18	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: rs776306463; hg19: chr9-111616980;