rs11692435

Variant names:

• chr2-97658891-G-A
• rs11692435
• NM_005735.4:c.428C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 1P and 8B. PP3 BA1

The NM_005735.4(ACTR1B):​c.428C>T​(p.Ala143Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0773 in 1,613,986 control chromosomes in the GnomAD database, including 6,471 homozygotes. In-silico tool predicts 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. A143G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.065 (646 hom., cov: 32)
  • Exomes 𝑓: 0.079 (5825 hom.)
• Consequence: ACTR1B NM_005735.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.86
• Publications: 57 publications found

Genes affected

ACTR1B (HGNC:168): (actin related protein 1B) This gene encodes a 42.3 kD subunit of dynactin, a macromolecular complex consisting of 10 subunits ranging in size from 22 to 150 kD. Dynactin binds to both microtubules and cytoplasmic dynein and is involved in a diverse array of cellular functions, including ER-to-Golgi transport, the centripetal movement of lysosomes and endosomes, spindle formation, chromosome movement, nuclear positioning, and axonogenesis. This subunit, like ACTR1A, is an actin-related protein. These two proteins, which are of equal length and share 90% amino acid identity, are present in a constant ratio of approximately 1:15 in the dynactin complex. [provided by RefSeq, Aug 2008]

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0833 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005735.4. 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
	ACTR1B	NM_005735.4	MANE Select	c.428C>T	p.Ala143Val	missense	Exon 5 of 11	NP_005726.1	P42025

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTR1B	ENST00000289228.7	TSL:1 MANE Select	c.428C>T	p.Ala143Val	missense	Exon 5 of 11	ENSP00000289228.5	P42025
	ACTR1B	ENST00000855774.1		c.428C>T	p.Ala143Val	missense	Exon 5 of 11	ENSP00000525833.1
	ACTR1B	ENST00000936776.1		c.428C>T	p.Ala143Val	missense	Exon 5 of 11	ENSP00000606835.1

Frequencies

GnomAD3 genomes AF: 0.0649 AC: 9874 AN: 152032 Hom.: 646 Cov.: 32

Gnomad AFR AF: 0.0119

Gnomad AMI AF: 0.0813

Gnomad AMR AF: 0.0409

Gnomad ASJ AF: 0.0357

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0139

Gnomad FIN AF: 0.246

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0851

Gnomad OTH AF: 0.0511

GnomAD2 exomes AF: 0.0700 AC: 17602 AN: 251390 AF XY: 0.0696

Gnomad AFR exome AF: 0.0115

Gnomad AMR exome AF: 0.0249

Gnomad ASJ exome AF: 0.0390

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.243

Gnomad NFE exome AF: 0.0887

Gnomad OTH exome AF: 0.0624

GnomAD4 exome AF: 0.0786 AC: 114874 AN: 1461836 Hom.: 5825 Cov.: 33 AF XY: 0.0768 AC XY: 55886 AN XY: 727224

African (AFR) AF: 0.0107 AC: 358 AN: 33480

American (AMR) AF: 0.0257 AC: 1150 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0389 AC: 1017 AN: 26136

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39700

South Asian (SAS) AF: 0.0165 AC: 1419 AN: 86258

European-Finnish (FIN) AF: 0.234 AC: 12501 AN: 53394

Middle Eastern (MID) AF: 0.00712 AC: 41 AN: 5762

European-Non Finnish (NFE) AF: 0.0851 AC: 94637 AN: 1111986

Other (OTH) AF: 0.0620 AC: 3744 AN: 60396

GnomAD4 genome AF: 0.0649 AC: 9875 AN: 152150 Hom.: 646 Cov.: 32 AF XY: 0.0708 AC XY: 5263 AN XY: 74352

African (AFR) AF: 0.0119 AC: 494 AN: 41554

American (AMR) AF: 0.0409 AC: 625 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0357 AC: 124 AN: 3472

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5172

South Asian (SAS) AF: 0.0141 AC: 68 AN: 4810

European-Finnish (FIN) AF: 0.246 AC: 2592 AN: 10544

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0851 AC: 5788 AN: 67988

Other (OTH) AF: 0.0506 AC: 107 AN: 2114

Alfa AF: 0.0713 Hom.: 1742

Bravo AF: 0.0485

TwinsUK AF: 0.0831 AC: 308

ALSPAC AF: 0.0825 AC: 318

ESP6500AA AF: 0.0159 AC: 70

ESP6500EA AF: 0.0833 AC: 716

ExAC AF: 0.0689 AC: 8371

Asia WGS AF: 0.00779 AC: 27 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Benign	0.0033	T
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	35
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-0.36	T
MutationAssessor	Pathogenic	4.1	H
PhyloP100		9.9
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.014	D
Polyphen		1.0	D
Vest4		0.36
MPC		1.2
ClinPred		0.089	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.71
Mutation Taster		=64/36	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.76		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.76		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs11692435; hg19: chr2-98275354; COSMIC: COSV56705212;