rs183820446

Variant names:

• chr7-150284755-T-G
• rs183820446
• NM_001164458.2:c.562A>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001164458.2(ACTR3C):​c.562A>C​(p.Lys188Gln) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000677 in 1,611,160 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000058 (0 hom.)
• Consequence: ACTR3C NM_001164458.2 missense, splice_region
• Scores: Splicing: ADA: 0.001316
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.29
• Publications: 0 publications found

Genes affected

ACTR3C (HGNC:37282): (actin related protein 3C) Predicted to enable ATP binding activity. Predicted to contribute to actin filament binding activity. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.040757895).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTR3C	NM_001164458.2	c.562A>C	p.Lys188Gln	missense_variant, splice_region_variant	Exon 6 of 8	ENST00000683684.1	NP_001157930.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTR3C	ENST00000683684.1	c.562A>C	p.Lys188Gln	missense_variant, splice_region_variant	Exon 6 of 8		NM_001164458.2	ENSP00000507618.1
ACTR3C	ENST00000252071.8	c.562A>C	p.Lys188Gln	missense_variant, splice_region_variant	Exon 6 of 8	1		ENSP00000252071.4
ACTR3C	ENST00000478393.5	c.556A>C	p.Lys186Gln	missense_variant, splice_region_variant	Exon 5 of 6	1		ENSP00000417426.1
ACTR3C	ENST00000539352.5	c.562A>C	p.Lys188Gln	missense_variant	Exon 5 of 5	5		ENSP00000440990.2

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152078 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000125 AC: 31 AN: 248234 AF XY: 0.000119

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000177

Gnomad ASJ exome AF: 0.00200

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000444

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000576 AC: 84 AN: 1458964 Hom.: 0 Cov.: 32 AF XY: 0.0000648 AC XY: 47 AN XY: 725650

African (AFR) AF: 0.00 AC: 0 AN: 33376

American (AMR) AF: 0.000249 AC: 11 AN: 44126

Ashkenazi Jewish (ASJ) AF: 0.00188 AC: 49 AN: 26074

East Asian (EAS) AF: 0.00 AC: 0 AN: 39646

South Asian (SAS) AF: 0.00 AC: 0 AN: 85396

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00000810 AC: 9 AN: 1110956

Other (OTH) AF: 0.000249 AC: 15 AN: 60278

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152196 Hom.: 0 Cov.: 32 AF XY: 0.000228 AC XY: 17 AN XY: 74428

African (AFR) AF: 0.00 AC: 0 AN: 41522

American (AMR) AF: 0.000588 AC: 9 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68002

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.000477 Hom.: 0

Bravo AF: 0.000283

ExAC AF: 0.0000906 AC: 11

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 28, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.562A>C (p.K188Q) alteration is located in exon 6 (coding exon 5) of the ACTR3C gene. This alteration results from a A to C substitution at nucleotide position 562, causing the lysine (K) at amino acid position 188 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.45
CADD	Uncertain	24
DANN	Benign	0.95
DEOGEN2	Benign	0.038	.;T;.
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.28	T;T;T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.038	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	.;L;.
PhyloP100		7.3
PROVEAN	Benign	-2.3	N;N;N
REVEL	Benign	0.13
Sift	Benign	0.26	T;T;T
Sift4G	Uncertain	0.049	D;T;T
Polyphen		0.074	.;B;.
Vest4		0.72, 0.59
MVP		0.15
MPC		0.37
ClinPred		0.10	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.27
gMVP		0.44
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0013
dbscSNV1_RF	Benign	0.0080
Splicevardb		2.0
SpliceAI score (max)		0.050		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: rs183820446; hg19: chr7-149981844;